Calcium Signaling in Neuronal Motility€¦ · a central role in the regulation of neuronal...

ANRV324-CB23-15 ARI 4 September 2007 23:52

Calcium Signaling inNeuronal MotilityJames Q. Zheng1 and Mu-ming Poo2

1Department of Neuroscience and Cell Biology, University of Medicine and Dentistryof New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854;email: [email protected] of Neuroscience, Department of Molecular and Cell Biology, Helen WillsNeuroscience Institute, University of California, Berkeley, California 94720;email: [email protected]

Annu. Rev. Cell Dev. Biol. 2007. 23:375–404

First published online as a Review in Advance onJune 20, 2007

The Annual Review of Cell and DevelopmentalBiology is online at http://cellbio.annualreviews.org

This article’s doi:10.1146/annurev.cellbio.23.090506.123221

Copyright c© 2007 by Annual Reviews.All rights reserved

1081-0706/07/1110-0375$20.00

Key Words

growth cone, axon guidance, regeneration, migration,synaptogenesis, synaptic plasticity

AbstractNeuronal motility is a fundamental feature that underlies the de-velopment, regeneration, and plasticity of the nervous system. Twomajor developmental events—directed migration of neuronal pre-cursor cells to the proper positions and guided elongation of axons totheir target cells—depend on large-scale neuronal motility. At a finerscale, motility is also manifested in many aspects of neuronal struc-tures and functions, ranging from differentiation and refinement ofaxonal and dendritic morphology during development to synapseremodeling associated with learning and memory in the adult brain.As a primary second messenger that conveys the cytoplasmic ac-tions of electrical activity and many neuroactive ligands, Ca2+ playsa central role in the regulation of neuronal motility. Recent studieshave revealed common Ca2+-dependent signaling pathways that aredeployed for regulating cytoskeletal dynamics associated with neu-ronal migration, axon and dendrite development and regeneration,and synaptic plasticity.

375

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Contents

INTRODUCTION. . . . . . . . . . . . . . . . . 376A PRIMER ON Ca2+

REGULATION INNEURONS . . . . . . . . . . . . . . . . . . . . . 376Ca2+ Homeostasis and Signaling . . 376Imaging Cytoplasmic Ca2+ . . . . . . . . 377

REGULATION AND GUIDANCEOF NEURONALMIGRATION . . . . . . . . . . . . . . . . . . . 379Various Forms of Neuronal

Migration . . . . . . . . . . . . . . . . . . . . . 379Ca2+ Channel Signaling in

Migrating Neurons . . . . . . . . . . . . 380Ca2+ Transients and Gradients . . . . 381

GROWTH CONE MOTILITYAND GUIDANCE . . . . . . . . . . . . . . 382Functions of Growth Cones . . . . . . . 382Ca2+ Signals Regulating Growth

Cone Motility and Turning . . . . 383DOWNSTREAM EFFECTORS OF

Ca2+ SIGNALS . . . . . . . . . . . . . . . . . . 384Ca2+-Dependent Kinases and

Phosphatases . . . . . . . . . . . . . . . . . . 384Ca2+-Dependent Adenylyl

Cyclases and Nitric OxideSynthase . . . . . . . . . . . . . . . . . . . . . . 385

Rho GTPases . . . . . . . . . . . . . . . . . . . . 386Other Cytoskeleton Regulatory

Proteins . . . . . . . . . . . . . . . . . . . . . . 386Adhesion Proteins . . . . . . . . . . . . . . . . 388

Ca2+ SIGNALING AND NEURITEBRANCHING. . . . . . . . . . . . . . . . . . . 389

Ca2+ AND AXONREGENERATION . . . . . . . . . . . . . . 390

SYNAPTOGENESIS ANDSYNAPSE REMODELING. . . . . . 391

CONCLUSION . . . . . . . . . . . . . . . . . . . . 393

INTRODUCTION

During early development, newly born neu-rons undergo extensive migration to set upthe ordered organization of the central andperipheral nervous systems (Bronner-Fraser1994, Hatten 1999, Kriegstein & Noctor

2004, Rakic 1995). Migration of these neuronsis terminated upon their arrival at the targetedregion and is followed by a period of nervegrowth that involves the elongation of a sin-gle axon and multiple dendrites, together withtheir extensive branching and arborization.Growing axons are led by a motile growthcone that navigates through the complex en-vironment of the developing tissue to reachthe appropriate region of the brain for es-tablishing selective synaptic contacts with tar-get neurons (Dickson 2002, Tessier-Lavigne& Goodman 1996). Although dendritic pro-cesses typically do not extend over long dis-tances, they nevertheless elaborate extensivebranches to cover a large field in order to cap-ture incoming axons and to establish synap-tic contacts (Cline 2001, Jan & Jan 2003,Tada & Sheng 2006). After synapses areestablished and become functional, furtherrefinement and remodeling of synaptic con-nections continue throughout the life of theanimal, involving the sprouting and retractionof axonal terminals and dendritic spines in anactivity-dependent manner (Gan 2003, Jontes& Smith 2000, Segal 2005). These diverseforms of neuronal motility—from cell migra-tion to synaptic remodeling—all depend onthe rearrangement of cytoskeletal structuresand can be regulated by specific extracellu-lar factors and intrinsic electrical activity in aspatiotemporally specific manner. In this re-view, we summarize recent progress in our un-derstanding of Ca2+ regulation of neuronalmotility, including neuronal migration, axongrowth and guidance, and dendritic remodel-ing. More extensive coverage on each of thesesubjects can be found in several recent reviews(Ayala et al. 2007, Bonhoeffer & Yuste 2002,Gomez & Zheng 2006, Henley & Poo 2004,Komuro & Kumada 2005, Segal 2005).

A PRIMER ON Ca2+

REGULATION IN NEURONS

Ca2+ Homeostasis and Signaling

Calcium ions act as a second messenger in-side the cell to mediate a wide spectrum

376 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


of cellular functions. At their resting state,cells maintain a baseline of intracellular Ca2+

concentration ([Ca2+]i) at approximately 100nM through Ca2+ homeostasis mechanisms.This basal concentration is crucial for cellsto respond effectively to various Ca2+ sig-nals elicited by extracellular stimuli or mem-brane depolarizations that often reach a con-centration of several hundreds of nanomolarto a few micromolar (Berridge et al. 2003,Clapham 1995). The resting level of [Ca2+]i ismaintained by Ca2+-ATPase-dependent up-take into internal stores (e.g., the endoplas-mic reticulum and mitochondria) and extru-sion out of the cell (Garcia & Strehler 1999) aswell as by the Na+/Ca2+ exchanger (Blausteinet al. 1991), which exchanges internal Ca2+

with extracellular Na+. The stimulus-inducedCa2+ signals originate from either Ca2+ influxof plasma membrane Ca2+ channels or Ca2+

release from internal stores. The best-knownCa2+ channels in the plasma membrane ofneurons are voltage-dependent Ca2+ channels(VDCCs) and neurotransmitter-gated chan-nels, many of which are involved in regulatingneuronal motility. Members of the transientreceptor potential (TRP) family of proteinsalso form ion channels that are permeantto Ca2+ (Clapham et al. 2001). These TRPchannels can be opened at the resting mem-brane potential and be regulated by extra-cellular signals, e.g., the neurotrophin brain-derived neurotrophic factor (BDNF) (Li et al.1999), or components of internal stores. De-pletion of intracellular Ca2+ stores can in-duce influx of Ca2+ from the extracellularspace through plasma membrane channels, amechanism known as store-operated Ca2+ en-try (SOCE) (Parekh & Putney 2005). Recentstudies have identified STIM and Orai pro-teins as the key components in SOCE opera-tion (Soboloff et al. 2006).

Although Ca2+ influx through the plasmamembrane conveys the first Ca2+ signal trig-gered by many extracellular stimuli, Ca2+ sig-nals are often amplified by further Ca2+ re-lease from internal stores. Such amplificationdepends on the process of Ca2+-induced Ca2+

VDCCs:voltage-dependentCa2+ channels

TRP: transientreceptor potential

BDNF:brain-derivedneurotrophic factor

SOCE:store-operated Ca2+entry

CICR:Ca2+-induced Ca2+release

release (CICR) mediated by the ryanodine-and IP3-sensitive channels in the membraneof the internal stores (Berridge et al. 2000).The Ca2+ ion diffuses very slowly in the cy-toplasm (diffusion coefficient at ∼10 μm2 s−1;see al-Baldawi & Abercrombie 1995, Murthyet al. 2000, Nakatani et al. 2002) owing tothe abundant immobile cytoplasmic Ca2+-binding proteins (Baimbridge et al. 1992,Blaustein 1988). Therefore, Ca2+ signals aretypically localized by limited diffusion butmay become global when substantial internalrelease is involved (Figure 1). Limited acti-vation of Ca2+ channels in the plasma mem-brane or the ER can result in high [Ca2+]i onlynear the channels, creating a microdomain of[Ca2+]i elevation or Ca2+ “sparks.” The spa-tiotemporal properties of cytoplasmic Ca2+

signals depend on the number and extentof activation of Ca2+ channels in both theplasma membrane and the membrane of in-ternal stores. The extended morphology ofneurons and diverse mechanisms for regulat-ing [Ca2+]i enable Ca2+ signals of differentspatiotemporal patterns to serve unique neu-ronal functions.

Imaging Cytoplasmic Ca2+

Studies of the dynamics of Ca2+ signaling inneurons were made possible by the develop-ment of Ca2+ indicators that reported [Ca2+]i

faithfully (Tsien 1980). The earlier forms ofthe indicators were based on derivatives ofsmall Ca2+ chelators, e.g., BAPTA, that re-sponded to Ca2+ binding by changes in thefluorescence quantum yield. More recent in-dicators are based on fluorescence resonanceenergy transfer (FRET) induced by a confor-mational change in calmodulin (CaM) uponbinding to Ca2+ (Miyawaki 2003, Miyawakiet al. 1997) and have the advantage of allow-ing expression in specific cells or subcellu-lar locations and in vivo imaging. Like manyother probes of cellular dynamics, the pertur-bation of these indicators on the spatiotem-poral pattern of endogenous [Ca2+]i is not al-ways negligible. Small mobile indicators may

www.annualreviews.org • Calcium Signaling in Neuronal Motility 377

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


a

b

–5 0 5

Time (s)

7 12

0 20 60

Time (ms)

100 140

10 µm

10 µm

Figure 1Different spatiotemporal patterns of Ca2+ signals in neurons. (a) Spatially restricted Ca2+ elevation byfocal laser–induced photolysis of caged Ca2+ in a Xenopus growth cone. The localized elevation of [Ca2+]was detected by fluo-3 imaging and displayed in pseudocolors. The color bar indicates the pseudocolorcoding of relative changes in fluo-3 intensity from 15% to 100% (from Zheng 2000). (b) An imagesequence of a Ca2+ wave from the growth cone to the soma, after frontal application of a Slit-2 gradient(white arrowheads). The [Ca2+]i was determined by the ratio of fluo-4 to Fura-Red fluorescence, coded bypseudocolors in a linear scale (from Guan et al. 2007).

speed up the diffusion of Ca2+ when theyare present at a concentration that signifi-cantly perturbs the buffering capacity of en-dogenous immobile Ca2+-binding proteins,thus distorting the spatial pattern of Ca2+ sig-nals. Even for low-mobility indicators, e.g.,dextran-coupled or FRET-based probes, theindicator may cause damping and prolongingof Ca2+ transients in some cell types when itsconcentration represents a significant fractionof the total Ca2+ buffering capacity (Berlinet al. 1994, Helmchen et al. 1996). Neurons

vary greatly in the content and buffering ca-pacity of Ca2+-binding proteins (Baimbridgeet al. 1992, Blaustein 1988), and thus the relia-bility of the indicator in a specific cell type de-pends on the concentration indicators loadedor expressed in the cell. In principle, a minimalamount of the indicator in the cytoplasm is de-sirable for the accurate detection of [Ca2+]i.Furthermore, special consideration should begiven to the acetoxymethyl ester (AM) form ofindicators because it can be loaded into sub-cellular compartments (e.g., organelles), thus

378 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


complicating the readout of cytoplasmic Ca2+

changes. Moreover, indicators with differentaffinities to Ca2+ should be selected to mon-itor a specific range of [Ca2+]i. Finally, nor-malization against the cell volume (e.g., theuse of a different fluorescent dye as the vol-ume marker) and calibration of the responsecurve of the Ca2+ indicator inside the cell arecrucial for proper readout of [Ca2+]i, a pro-cedure that is rather difficult for GFP-basedprobes in vivo.

REGULATION AND GUIDANCEOF NEURONAL MIGRATION

Various Forms of NeuronalMigration

During early development, newly generatedprecursor cells for principal cortical neuronsmigrate on the surface of radial glial cells fromthe ventricular zone to reach the superficialregion of the cortical plate, where such pre-cursor cells form the layered structure of thecortex. In contrast, precursor cells for diversepopulations of interneurons migrate overlong distances from ganglionic eminences tothe cortex via tangential migratory routes(Corbin et al. 2001, Hatten 1999, Kriegstein& Noctor 2004, Maricich et al. 2001, Marin& Rubenstein 2001, Rakic 1995). Neural crestcells that emerge from the dorsal margin ofthe neural tube migrate over long distancesalong specific routes to form sensory, auto-nomic, and enteric ganglia in the peripheralnervous system (Bronner-Fraser 1994). Allthese migratory movements are apparentlyguided by extracellular guidance signals andtheir interactions with other cells in the devel-oping tissue (Hatten 1999, Park et al. 2002).

Many migrating neurons exhibit a highlypolarized morphology: They have leading andtrailing neurite processes. Directed move-ment of the neuron typically requires threedistinct steps: extension of the leading process,translocation of the soma/nucleus, and retrac-tion of the trailing process (Figure 2a). Theleading process is headed by a growth cone–

like structure similar to the motile axonalgrowth cone. Successful migration of the cellalso requires the translocation of the soma.This involves the detachment of the somaticadhesion to the substrate and the movementof the nucleus (nucleokinesis) and many othercytoplasmic organelles (Ayala et al. 2007),which in turn may involve mechanisms dis-tinct from those operating at the growthcone. In vitro observations of cultured cere-bellar granule cells indicate that both the lead-ing growth cone and the soma exhibit salta-tory but coordinated advancement (Hatten1999).

It is not clear whether both the leadinggrowth cone and the soma detect the direc-tional signals from the environment. If onlythe leading growth cone is responsible forthe signal detection, as suggested by recentfindings regarding cultured cerebellar gran-ule cells (Guan et al. 2007), a long-range sig-naling mechanism between the growth coneand the soma is required for proper coordina-tion of the motility of these two distant partsof the neuron. Furthermore, coordinated re-traction of the trailing processes as the leadingprocess advances forward must involve actin-based contractile machinery and degradationof the adhesion complex, as suggested by stud-ies of migration of nonneuronal cells (Horwitz& Parsons 1999, Sheetz et al. 1998, Wittmann& Waterman-Storer 2001). In migrating cere-bellar granule neurons in vivo, the trailingprocesses represent the immature axonal pro-jections and do not retract as the cell bodymoves toward the inner granular layer. In thiscase, how the migrating neuron handles thetension built up owing to the “stretched” mor-phology may have some impact on the dis-tance of migration. In short, cytoplasmic sig-naling among the leading process, soma, andtrailing process is essential for the directedmovement of migrating neurons. The molec-ular mechanisms underlying the guidance andmotility of neuronal migration have been ex-tensively reviewed recently (Ayala et al. 2007).Therefore, we focus here on the role of Ca2+

signaling.


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


a

N

[Ca

2+] i

b

LP TA

F

? ?

R

40 µm

Figure 2Directed cell migration and Ca2+ signals. (a) A time-lapse sequence of a cerebellar granule neuron thatexhibits directional migration on a laminin stripe ( J.Q. Zheng, unpublished data). The time lapse wasperformed at a rate of one frame every 5 min. The yellow dotted line indicates the original position of thesoma. (b) Schematic illustrations of the possible link between Ca2+ signals and directional cell migration.The bipolar migrating neuron exhibits a leading process (LP) and a trailing axon (TA). Repetitivefluctuations of [Ca2+]i have been associated with the movement of the soma. It remains unclear whetherthe LP and TA exhibit any Ca2+ transients or gradients during migration. However, many chemotacticnonneuronal cells exhibit a rear (R)-to-front (F) Ca2+ gradient, which is believed to be involved incontraction and detachment of the real tail during cell movement. N denotes nucleus. The color gradientrepresents the level of [Ca2+]i.

Ca2+ Channel Signaling in MigratingNeurons

Evidence for a Ca2+ role in neuronal migra-tion first came from imaging studies of gran-ule cell migration in acute mouse cerebellarslices, in which blockade or enhancement ofCa2+ influx through N-type VDCCs or theN-methyl-d-aspartate (NMDA) subtype ofthe glutamate receptor reduced or promotedthe rate of granule cell movement, respec-tively (Komuro & Rakic 1992, 1993). In sup-port of this finding, depletion and elevationof extracellular Ca2+ result in the impedimentand acceleration of granule cell migration, re-spectively. Similar ion channel involvement

has also been reported for the migration ofother cell types, e.g., gonadotropin-releasinghormone-1 (GnRH-1) neurons (Toba et al.2005). Interestingly, different VDCCs may beinvolved in Ca2+ signaling for axon guidanceand neuronal migration. In Caenorhabditiselegans, Tam et al. (2000) found that in mutantscarrying loss-of-function alleles of the VDCCgene unc-2, the touch receptor neuron AVMand the interneuron SDQR exhibit aberrantsoma translocation, but AVM neurons extendaxons normally, suggesting that the UNC-2VDCC specifically directs soma translocationand is not required for axonal pathfinding. Incontrast, mutations in egl-19, which encodesanother VDCC, affect soma translocation of

380 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


the AVM and SDQR as well as the guidanceof the AVM axon.

Ca2+ Transients and Gradients

Ca2+ imaging has revealed different patternsof Ca2+ transients in the soma of cerebellargranule cells during different phases of salta-tory movement (Komuro & Kumada 2005).Forward movement and stationary state aretightly correlated with the peak and troughof the Ca2+ fluctuation, respectively, and therate of soma translocation positively corre-lates with both the amplitude and frequencyof Ca2+ transients under a variety of pharma-cological treatments that perturb these tran-sients (Komuro & Kumada 2005, Komuro &Rakic 1996). Interestingly, these Ca2+ tran-sients disappear approximately 10 min beforethe granule cells terminate their migrationin the inner granule layer in the cerebellum(Kumada & Komuro 2004). The spontaneousCa2+ transients in migrating granule cells aremediated by NMDA receptors and N-typeVDCCs (Komuro & Kumada 2005), whichmay be activated by the ambient endogenousglutamate in the extracellular space. In addi-tion, the endogenous GABA may also con-tribute to the Ca2+ fluctuations by activatingdepolarizing currents through GABAA recep-tors. This excitatory action of GABA is due tothe high intracellular Cl− concentration thatresults from the low-level expression of theCl− transporter KCC2 (Ganguly et al. 2001,Rivera et al. 1999). Excitatory GABAergic ac-tivities have been observed in various regionsof the developing brain (Ben-Ari 2002), andin vitro studies suggest that GABA may regu-late cortical neuron migration via the activa-tion of GABAA receptors (Behar et al. 1996,2000). Finally, the neuropeptide somatostatinappears to influence Ca2+ fluctuations in cere-bellar granule neurons in a stage-dependentmanner (Yacubova & Komuro 2002b). So-matostatin appears to enhance Ca2+ tran-sients to accelerate the migration of imma-ture granule cells, but attenuate Ca2+ spikes toslow down the cells reaching their destination.

Given the complex environment in the devel-oping brain, it is conceivable that neuronalmigration is influenced by a combination ofextracellular factors as well as intrinsic neu-ronal activities (Yacubova & Komuro 2002a).

Although Ca2+ transients regulate thesoma movement during migration, it re-mains unclear whether Ca2+ signals con-vey directional instructions for cell migration(Figure 2b). Using dissociated neurons fromthe ganglionic eminences, the source of tan-gentially migrating neurons that give rise tocortical interneurons, Moya & Valdeolmillos(2004) showed that soma translocation is as-sociated with an increase in [Ca2+]i; a higherCa2+ elevation occurs in the proximal re-gion of the leading process, a zone with awide distribution of γ-tubulin. The impor-tance of the spatial pattern of cytoplasmicCa2+ is suggested by the finding that uni-form [Ca2+]i elevation by transmitter perfu-sion did not elicit nucleokinesis. In directedmigration of zebrafish primordial germ cellsin response to the chemokine stromal-derivedfactor-1 (SDF-1), polarized activation of thereceptor CXCR4 leads to frontal elevation of[Ca2+]i, which appears to activate myosin con-traction and results in the formation of bleb-like protrusions at the front of the cell (Blaseret al. 2006). Furthermore, polarized migrat-ing germ cells displayed a high [Ca2+]i at thecell front, but cells with CXCR4b downreg-ulated showed lower [Ca2+]i at the front andnondirectional migration. These observationsindicate that a Ca2+ gradient across the cellbody may provide the directional clue for cellmigration.

Many chemotactic cells, however, displaya stable Ca2+ gradient of a reverse (tail-to-front) direction (Brundage et al. 1991, Fayet al. 1995, Gilbert et al. 1994, Laffafian &Hallett 1995), which likely involves Ca2+ re-lease from internal stores (Fay et al. 1995) andinflux through stretch-activated Ca2+ chan-nels (Lee et al. 1999). Such a rear-to-frontCa2+ gradient is believed to be responsiblefor the retraction and detachment of the reartail during the forward movement of the cell


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


(Figure 2b). The discrepancy in the polarityof Ca2+ gradients in different migrating cellsmay reflect different spatiotemporal proper-ties of Ca2+ signals that may target distinctdownstream pathways for specific functions(e.g., directional sensing versus movement).

Using single isolated granule cells growingon the surface of cocultured radial glial cells,Xu et al. (2004) found that local application ofSlit-2, a well-known repellent for growth coneand migration neurons, in front of the migrat-ing granule cell resulted in a front-to-backgradient of intracellular Ca2+ in the soma.This somatic Ca2+ gradient appeared to be re-quired for the reversal of soma translocationon the glial cell. To simplify this experimentalsystem further, Guan et al. (2007) used iso-lated granule cell migrating on the surface ofculture substratum to examine Slit-2-inducedCa2+ signals. They found that Slit-2 induces apropagating Ca2+ wave from the growth coneof the leading process to the soma. Initiationof a propagating Ca2+ wave requires CICRfrom the interval stores. These findings areconsistent with the rear-to-front Ca2+ gradi-ent in chemotactic cells in which high [Ca2+]i

is involved in the retraction and detachmentof the rear tail. Thus, basal [Ca2+]i in migrat-ing cells, maintained by Ca2+ influx throughplasma membrane Ca2+ channels, providesthe necessary conditions for global cellularmotility, whereas Ca2+ signals triggered byguidance cues serve to alter the direction-ality of neuronal migration. What remainsto be seen is whether specific Ca2+ signalsmay provide the directional cue for migratingneurons in vivo. The difficulty in performingCa2+ imaging of the entire migrating neuronin vivo, including the leading and trailing pro-cesses, represents a major obstacle to addressthis important question (Figure 2b).

GROWTH CONE MOTILITYAND GUIDANCE

Functions of Growth Cones

First discovered by Ramon y Cajal more thana century ago (Ramon y Cajal 1890), growth

cones are specialized motile endings of ax-ons and dendrites that are responsible foraxon/dendrite growth and pathfinding in vivo.Upon the growth cone’s arrival at the tar-geted region, contact with the appropriate tar-get cell transforms the growth cone from ahighly motile structure into a stable presy-naptic terminal specialized for the secretionof neurotransmitters and neuromodulators.Each growth cone has a peripheral region(P-region), consisting of lamellipodia andfilopodia, and a central region (C-region) atthe end of the neurite shaft (Figure 3a).Lamellipodia and filopodia are actin-basedmotile structures (Figure 3b) that constantlyundergo rapid protrusion/retraction and gen-erate the traction force for advancing thegrowth cone (Forscher & Smith 1988). TheC-region of the growth cone is enrichedwith bundles of microtubules (MTs), some ofwhich extend into the P-region (Figure 3b).The C-region is also loaded with cellular or-ganelles and vesicles and believed to be theterminal station of vesicular trafficking andthe primary site for endo- and exocytic ac-tivities. Successful elongation of the neuriteprocess requires actin-based growth cone ad-vance followed by subsequent forward move-ment of the C-region and consolidation of thenewly extended segment into the stable neu-rite shaft. The interactions between the actinfilaments and MTs are crucial to growth conemotility (Rodriguez et al. 2003).

During development, early-emerging pi-oneer axons are responsible for establishingthe major routes for axon extension, on thebasis of diffusible or contact-mediated attrac-tive and repulsive cues provided by the en-vironment (Dickson 2002, Tessier-Lavigne &Goodman 1996). Many follower axons maytake advantage of the situation by adheringto pioneer axons via homophilic adhesion.Growth cones typically exhibit a wide rangeof behaviors along the path of elongation, in-cluding variations in extension rate, pausing,collapse, retraction, bifurcation, and fascicu-lation and defasciculation. Many of these dis-tinct behaviors reflect growth cone responses

382 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


a b

10 µm10 µm

C

P

Filopodia

Lamillopodia

Figure 3The morphology and cytoskeleton of the nerve growth cone. (a) A differential interference contrast(DIC) image of a Xenopus growth cone depicting the peripheral (P) and central (C) regions. (b) Thefluorescent image of a Xenopus growth cone exhibiting the microtubules (MTs) ( green) and the actinfilaments (red ). MTs were immunostained, and the actin filaments were labeled by rhodamine-phalloidin.

to local environmental cues and can be repli-cated in cell cultures for studying the un-derlying cellular mechanisms (Supplemen-tal Video 1; follow the Supplemental Mate-rial link from the Annual Reviews home pageat http://www.annualreviews.org). Growthcone migration and guidance are essential fornot only the initial wiring of neural circuitrybut also the rewiring and functional recov-ery of nerve connections after injury, althoughthe tissue terrain for pathfinding of regenerat-ing axons is quite different between adult andembryonic tissues. The similarity of signalingmechanisms underlying growth cone motilityof developing and regenerating axons suggeststhat our understanding of axon guidance dur-ing development may help to formulate thera-peutic strategies that can promote the regen-eration of injured axons and the recovery ofneural circuit connectivity and function.

Ca2+ Signals Regulating GrowthCone Motility and Turning

Ca2+ is a key regulator of growth cone motilityand mediates the actions of many extracellular

molecules in axonal elongation and guidance(Gomez & Zheng 2006, Henley & Poo 2004).Although an optimal range of [Ca2+]i is re-quired for growth cone extension (Kater et al.1988), spontaneous fluctuations of [Ca2+]i inthe forms of Ca2+ waves and spikes regu-late the rate of axonal elongation in develop-ing Xenopus axons in a frequency-dependentmanner (Gomez & Spitzer 2000, Gomez& Zheng 2006). In directional guidance ofgrowth cone extension, spatially restricted cy-toplasmic Ca2+ signals mediate both attractiveand repulsive responses of growth cones toseveral extracellular guidance cues (Figure 4).Recent studies indicate that different spa-tiotemporal patterns of Ca2+ signals accountfor the action of Ca2+ in triggering oppositemotile behaviors of growth cones: A small lo-cal Ca2+ elevation (or shallow gradient acrossthe growth cone) triggers growth cone repul-sion, whereas a modest local elevation inducesgrowth cone attraction (Henley et al. 2004,Wen et al. 2004). However, relatively largelocal Ca2+ transients also cause growth conerepulsion (Robles et al. 2003). These findingsindicate the existence of at least three ranges


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


?

GuidanceGuidancemoleculesmoleculesGuidancemolecules

1 2 3 5

6

4

[Ca

2+] i

Figure 4Schematic diagram illustrating the potential functions of Ca2+ in various motility activities associatedwith neuronal development. Different labels indicate specific events that involve distinct patterns of Ca2+signals: (1) growth cone extension and turning, (2) collateral branching, (3) axotomy, (4) growth coneregeneration, (5) dendritic branching and patterning, and (6 ) spine dynamics and synaptic plasticity. Thestructures highlighted by dotted lines in step 4 indicate degenerating parts of the axon after axotomy.

of local Ca2+ signals involved in growth conesteering—small and large Ca2+ signals for re-pulsion and modest Ca2+ signals for attrac-tion (Gomez & Zheng 2006)—which is con-sistent with the previous model of optimalCa2+ range for growth cone motility (Kateret al. 1988). Therefore, Ca2+ signals, whenpresent globally in the growth cone, can reg-ulate overall growth cone motility and rateof extension but, when locally elicited on oneside of the growth cone, can induce asymmet-ric growth cone motility that leads to steeringof the growth cone.

DOWNSTREAM EFFECTORS OFCa2+ SIGNALS

How does a Ca2+ signal modulate neuronalmigration and axon guidance? Ultimately,Ca2+ signals must act upon the cytoskeletal

dynamics (the actin and MTs) and theneuron’s adhesion to its substrate to controlmotility. The list of known targets for Ca2+

signaling is long and has been reviewedextensively elsewhere (see reviews by Gomez& Zheng 2006, Henley & Poo 2004). Herewe focus on several main targets that regulatethe cytoskeletal dynamics and cell-substrateadhesion for neuronal migration and axonguidance.

Ca2+-Dependent Kinases andPhosphatases

The best-known proteins that can directlybind and respond to Ca2+ are those thatcontain the EF-hand Ca2+-binding motif(Grabarek 2006), of which CaM representsto the most intriguing Ca2+ sensor that is in-volved in a diverse array of Ca2+-dependent

384 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


cellular responses, especially those in neurons.Upon Ca2+ binding, Ca2+/CaM can asso-ciate with a wide range of targets, includ-ing a number of kinases and phosphates,to elicit diverse signaling cascades (Chin &Means 2000, Crivici & Ikura 1995, Hoeflich& Ikura 2002). Multifunctional Ca2+/CaM-dependent protein kinases (CaMKs) comprisethree enzymes referred to as CaMKI, II, andIV (Hanson & Schulman 1992, Tombes et al.2003). CaMKII is highly enriched in the nervetissues and critical for neural development(Griffith 2004). CaMKII comprises a fam-ily of 28 similar isoforms that are derivedfrom four genes (α, β, γ, and δ), and theα- and β-subunits are expressed predomi-nately in the brain (Hudmon & Schulman2002). Among different CaMKII isoforms,β-CaMKII is of particular interest because itis often expressed in the early developmen-tal stages, anchored to the actin cytoskeleton,and capable of regulating neurite extension(Fink et al. 2003). Importantly, β-CaMKIIrequires several-fold-lower Ca2+/CaM con-centrations for activation compared with theα isoform (Brocke et al. 1999), making theformer ideal for sensing small Ca2+ signalsduring guidance responses (Wen et al. 2004,Zheng et al. 1994). In contrast, α-CaMKIImediates axonal branching induced by largeCa2+ transients (Tang & Kalil 2005), andCaMKI regulates axonal extension and den-dritic development (Wayman et al. 2004,2006). Moreover, nucleus-localized CaMKIVplays a role in activity-dependent transcrip-tion regulation in neurons (Impey et al. 2002).Finally, in C. elegans, similar phenotypes oftouch neuron and interneuron migration werefound for mutants carrying loss-of-functionmutations of VDCC gene unc-2 and the unc-43/CaMK gene, suggesting that CaMK me-diates unc-2-dependent Ca2+ signaling (Tamet al. 2000). Therefore, different membersand isoforms of CaMKs are involved in dis-tinct aspects of Ca2+-dependent regulation ofneuronal development.

Ca2+ elevations also activate phosphatases,of which phosphatase 2B, or calcineurin, is

CaMK:Ca2+/calmodulin-dependentkinase

AC: adenylyl cyclase

NOS: nitric oxidesynthase

the only known Ca2+/CaM-dependent phos-phatase. Calcineurin is activated by Ca2+ sig-nals of lower magnitude than those activat-ing CaMKs. Long-term regulation of axonaloutgrowth by netrin-1 and neurotrophin in-volves the activation of the transcription fac-tor NFAT by calcineurin (Graef et al. 2003).Over short-term periods, global Ca2+ tran-sients inhibit neurite extension via calcineurin(Lautermilch & Spitzer 2000), and localized[Ca2+]i elevation at a low level acts on cal-cineurin, which in turn activates phosphatase-1 to induce repulsive growth cone turning(Wen et al. 2004). Thus, different Ca2+ sig-nals may function through calcineurin to ac-tivate different downstream pathways and toelicit short- and long-term effects on growthcone extension and guidance.

Ca2+-Dependent Adenylyl Cyclasesand Nitric Oxide Synthase

Ca2+ can regulate the production of cAMPand cGMP, two important second messen-gers, via its action on adenylyl cyclases (ACs)and nitric oxide synthase (NOS), respectively.Out of the nine known AC isoforms, fourare regulated by submicromolar concentra-tions of Ca2+: AC1 and AC8 are stimulated byCa2+/CaM, and AC5 and AC6 are directly in-hibited by Ca2+ (Cooper 2005, Cooper et al.1995). In HEK293 cells expressing the type8 AC, induction of Ca2+ oscillations by elec-trical or agonist stimulation resulted in pe-riodic changes in cAMP through the activa-tion of Ca2+-dependent AC and subsequentprotein kinase A (PKA)-mediated phospho-diesterase 4 activity (Willoughby & Cooper2006). In developing Xenopus spinal neuronsin culture, a train of action potentials initi-ated in a neuron can modify the subsequentgrowth cone turning responses to extracellu-lar guidance cues, a process mediated by theelevation of cAMP, presumably through ACactivation (Ming et al. 2001). Gorbunova &Spitzer (2002) also found that the stimulationof specific patterns of Ca2+ transients in theseneurons resulted in the generation of cAMP


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


NO: nitric oxide

GEFs: guaninenucleotide exchangefactors

GAPs:GTPase-activatingproteins

transients, whereas blocking Ca2+ transientsabolished spontaneous cAMP transients. Be-cause both VDCCs and Ca2+ release channelsin the internal stores can be regulated by PKAas well, Ca2+ and cAMP signals may interactin a reciprocal manner.

Nitric oxide (NO) is a short-lived gaseousmessenger that activates guanylyl cyclase,leading to the activation of various cGMP-dependent pathways (Dawson & Snyder1994). NO is synthesized by three differentisoforms of NOS. Neuronal NOS (nNOS)is associated with postsynaptic density andtranslocated to the cytoplasm upon bind-ing with the Ca2+/CaM complex. Phospho-rylation by CaMKII inhibits, and dephos-phorylation by calcineurin activates, nNOS(Dawson et al. 1998). Thus, Ca2+ signalsmay either up- or downregulate the ac-tivity of cGMP-dependent pathways. TheNO/cGMP/protein kinase G signaling path-ways do indeed regulate neurite growth (Ernstet al. 2000, Renteria & Constantine-Paton1996, Trimm & Rehder 2004) and neuronalmigration (Haase & Bicker 2003).

Rho GTPases

The Rho family of GTPases, includingCdc42, Rac, and Rho, is essential for directedmotility during neurite extension, axon guid-ance, and neuronal migration (Fukata et al.2003, Luo 2000). There is evidence that RhoAis involved in growth cone collapse and re-pulsion whereas Rac and Cdc42 participatein growth cone attraction (Dickson 2001). InXenopus cultures, the activation of Cdc42 andRac mediates attractive growth cone turninginduced by BDNF, whereas RhoA mediatesthe repulsive turning induced by lysophospha-tidic acid (Yuan et al. 2003). Guan et al. (2007)found that the reversal of neuronal migrationinduced by Slit-2 requires a propagating Ca2+

wave from the growth cone of the leading pro-cess to the soma as well as the activity of RhoA,but not Cdc42 or Rac activity. RhoA accu-mulates at the front of the migrating neuron,and this polarized RhoA distribution is re-

versed during the migration reversal inducedby Slit-2 or by the propagating Ca2+ wave.Furthermore, Slit-2 downregulates RhoA ac-tivity in a Ca2+-dependent manner ( Jin et al.2005). These results suggest that long-rangeCa2+ signaling coordinates the Slit-2-inducedchanges in motility at the two distant parts ofmigrating neurons by regulating RhoA distri-bution.

How do distinct Ca2+ signals differen-tially regulate Rho GTPases? Rho GTPasesare regulated by large families of gua-nine nucleotide exchange factors (GEFs) andGTPase-activating proteins (GAPs). Recentevidence indicates that Ca2+ can regulateRho GTPases through Ca2+-regulated GAPsand GEFs (Aspenstrom 2004). In addition,CaMKII and protein kinase C (PKC), whichcan both be activated by Ca2+, can also acti-vate Rho GTPases (Fleming et al. 1999, Priceet al. 2003). Conversely, Rho GTPase activitymay act upstream to regulate [Ca2+]i. For ex-ample, the inhibition of Rho, but not of Rac orCdc42, impaired the migration of hematopoi-etic stem cells toward chemokine SDF-1, ap-parently by inhibiting SDF-1-induced Ca2+

transients (Henschler et al. 2003). Such recip-rocal activation between Ca2+ signal and RhoGTPase activity provides a potential positivefeedback mechanism required for the stablelocal activation of neuronal motility.

Other Cytoskeleton RegulatoryProteins

The structures and dynamics of MTs and theactin cytoskeleton are regulated by a vari-ety of associated proteins (Dent & Gertler2003, Korey & Van Vactor 2000, Meyer& Feldman 2002); many of them can beregulated and/or influenced by intracellularCa2+ signals (Gomez & Zheng 2006, Henley& Poo 2004). Myosin light chain kinase(MLCK), a member of the CaMK family, isdirectly activated by Ca2+/CaM to phospho-rylate myosin light chain and regulate acto-myosin contractility, which has been shownto mediate growth cone retraction (Gallo

386 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


et al. 2002, Schmidt et al. 2002, Zhou &Cohan 2001) and directed cell migration (Leeet al. 1999). Given the importance of myosinmolecules, especially myosin II, in growthcone motility and guidance (Medeiros et al.2006, Ruchhoeft & Harris 1997, Turney &Bridgman 2005), Ca2+ regulation of myosinactivity may represent an important mech-anism for Ca2+ regulation of growth conemotility. Gelsolin is another example of actin-regulatory proteins that can be activated di-rectly by Ca2+ signals (Lu et al. 1997). Inaddition to direct activation by Ca2+, manyactin-associated proteins can be regulated byCa2+ through cross talk with distinct sig-naling pathways, especially Rho GTPases.For example, the myosin pathway canbe regulated by Rho-associated coiled-coil-containing kinase (ROCK), p21-activated ki-nase (PAK), and PKC, all of which can beactivated by Ca2+ signals (see Henley & Poo2004).

Another interesting example is the actin-depolymerizing factor (ADF)/cofilin family ofproteins, which were initially identified fortheir ability to increase the rate of dissocia-tion of ADP-actin from the pointed end ofactin filaments to promote depolymerization(Carlier et al. 1997) and to sever actin fila-ments into small fragments for disassembly(Maciver 1998). Recent studies, however, in-dicate that ADF/cofilin severing of actin fil-aments at the leading edge of the nonneu-ronal cells may generate new filament endsto promote the nucleation and assembly ofactin filaments, which in turn drive mem-brane protrusion and cell migration (Kuhnet al. 2000, Pollard et al. 2000). WhetherADF/cofilin promotes filament assembly ordisassembly depends on a number of dif-ferent factors that influence the nucleation,polymerization, and stabilization of actin fil-aments. In neurons, ADF/cofilin is expressedat high levels, colocalizes with F-actin in thegrowth cone (Bamburg & Bray 1987), andis involved in neurite outgrowth (Meberget al. 1998) and growth cone collapse (Aizawaet al. 2001, Hsieh et al. 2006, Piper et al.

ROCK:Rho-associatedcoiled-coil-containing proteinkinase

PAK: p21-activatedkinase

ADF: actin-depolymerizingfactor

MAPs:microtubule-associatedproteins

2006). ADF/cofilin molecules are inhibited byphosphorylation on a highly conserved serineresidue, Ser3 (Agnew et al. 1995), by LIM ki-nases LIMK1 and LIMK2, which are down-stream of Rho GTPases (Kuhn et al. 2000). Itis thus reasonable to speculate that Ca2+ sig-nals may act through Rho GTPases to controlLIM kinase activation, regulating the activ-ity of ADF/cofilin. Furthermore, ADF/cofilinis activated through dephosphorylation bySlingshot phosphatases (Niwa et al. 2002),which can be activated by the Ca2+/CaM-dependent phosphatase calcineurin (Huanget al. 2006). Therefore, ADF/cofilin may rep-resent a converging target of multiple signal-ing cascades that regulates actin dynamics inthe growth cone. Taken together, differentspatiotemporal patterns of Ca2+ signals mayelicit and act upon divergent signaling path-ways that converge on the actin cytoskele-ton to regulate growth cone motility andguidance.

Guidance signaling can also target thedynamics of MTs to control and influencegrowth cone extension and guidance (Kalil& Dent 2005, Korey & Van Vactor 2000).Local manipulation of MT dynamics is suf-ficient to trigger bidirectional growth coneturning (Buck & Zheng 2002). Ca2+ signalscan regulate MT dynamics through the bind-ing of Ca2+/CaM to specific MT-associatedproteins (MAPs) (Dehmelt & Halpain 2004).Furthermore, the MAPs MAP2 and tau, uponphosphorylation and dephosphorylation byCaMKII and calcineurin phosphatase, canshow different binding affinities for MTs,resulting in the modification of MT sta-bility (Goto et al. 1985, Mandelkow et al.1995, Yamamoto et al. 1985). Moreover,the growth cone–associated protein GAP43is the target of CaMKII and calcineurin(Lautermilch & Spitzer 2000). Finally, guid-ance cues can control growth cone motil-ity and guidance through the regulationof the dynamic plus ends of MTs (Leeet al. 2004, F.Q. Zhou et al. 2004). TheCa2+-sensitive GTPase-scaffolding proteinIQGAP1 interacts with the plus-end-binding


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Cdk5:cyclin-dependentkinase 5

protein CLIP170 to capture MT ends tothe cortical actin cytoskeleton (Fukata et al.2002). Ca2+-dependent interactions of Lis1with IQGAP1 and Cdc42 promote neuronalmigration (Kholmanskikh et al. 2006). There-fore, Ca2+ signals may regulate MT dynamicsthrough distinct mechanisms to control andinfluence growth cone motility and guidanceresponses. Finally, the unconventional cyclin-dependent kinase 5 (Cdk5) regulates the mi-gration of postmitotic neurons through theremodeling of the microtubule cytoskeleton(Hirasawa et al. 2004, Xie et al. 2006). Recentstudies indicate, however, that Cdk5 can alsoregulate the actin cytoskeleton through RhoGTPases (e.g., PAK1 and p27kip1) or WAVE1(Kawauchi et al. 2006, Kim et al. 2006). Apotential link between Ca2+ and Cdk5 camefrom the findings that glutamate can induce atransient Ca2+/CaM-dependent activation ofCdk5 in hippocampal slices, through the acti-vation of NMDA or kainate receptors (Weiet al. 2005). It is thus intriguing to specu-late that Cdk5 may represent a multifunc-tional molecule that regulates both cytoskele-tal structures underlying Ca2+ control of neu-ronal motility.

Adhesion Proteins

Directional migration of both the neuron andthe growth cone requires a spatiotemporallycoordinated establishment of new focal adhe-sions by the advancing front and the disas-sembly of existing ones at the trailing end.It is largely unclear how cytoplasmic sig-naling mechanisms achieve such coordinatedregulation of focal adhesions during directedmovement, a problem particularly acute forneurons that exhibit relatively long leadingand trailing processes. Neurons in vivo ad-here to their interacting cells through ei-ther homo- or heterophilic interactions be-tween cell adhesion molecules (CAMs) onthe surface. For neurons migrating on thesurface of radial glial cells, astrotactin, inte-grin, and neuregulin are involved, whereashomophilic neuron-neuron adhesion is me-

diated by N-CAM and cadherin. For propermigration, the extent of substrate adhesionmust be optimal—sufficient adhesion is re-quired for the cell to exert enough tractionforce to move, yet too much adhesion mayimmobilize the cell. In cultured Swiss 3T3fibroblasts, Rac, Cdc42, and Rho are all in-volved in regulating cell adhesion to the sub-strate (Nobes & Hall 1995), although Racand Cdc42 activation leads to the assemblyof focal adhesion complexes associated withlamellipodia and filopodia, distinct from thoseinduced by Rho activation. Nobes & Hall(1995) propose that the activation of thesethree GTPases may be linked in a hierar-chical manner during the process of cell mi-gration: Activation of Cdc42 leads to the in-duction of filopodia and to Rac activationand lamellipodia formation. Rac in turn ac-tivates Rho, leading to the assembly of newadhesion sites and of stress fibers that enablecell contraction and retraction of the trail-ing tail. In nerve growth cones, the regulationof point adhesion contacts by Rho GTPasesis important for neurite outgrowth (Woo &Gomez 2006). Ca2+ signals therefore may actthrough Rho GTPases to target adhesion ina spatiotemporal fashion to regulate neuronalmotility.

Microtubule targeting of focal adhesionsis known to trigger their disassembly, but dy-namin and focal adhesion kinase, rather thanRho inhibition, apparently mediate disassem-bly (Ezratty et al. 2005). Because dynaminregulates endocytosis, the disassembly of fo-cal adhesions may involve endocytic removalof adhesion molecules from the plasma mem-brane, consistent with the observed endocy-tosis of integrins in migrating cells (Panickeret al. 2006). Endocytic recycling of themembrane is Ca2+ dependent, providing amechanism by which Ca2+ signaling mayregulate cell migration through the modu-lation of substrate adhesion. Finally, adhe-sion may also provide feedback regulation ofCa2+ signals in the cell. Ooashi et al. (2005)found that in cultured dorsal root ganglionneurons CAMs can regulate the activity of

388 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


ryanodine receptor type 3 (RyR3) via cAMPand activation of PKA, resulting in CICRthat causes attractive turning of the growthcone. A recent study also showed that local-ized Ca2+ signals induce asymmetric exocy-tosis to result in a turning response (Tojimaet al. 2007). In cultured cerebellar granulecells, rapid signaling via the propagation ofa Ca2+ wave from the leading growth coneto the soma conveys the reversal signal trig-gered by frontal application of Slit-2, in a pro-cess that involves front-to-rear redistributionof RhoA activity (Guan et al. 2007). How suchRhoA redistribution affects focal adhesions tothe substrate during the reversal process andwhat is the signal responsible for coordinatingthe forward-migration process remain to beelucidated.

Ca2+ SIGNALING AND NEURITEBRANCHING

Branching of axonal and dendritic processesis an essential step for the wiring of complexneuronal circuitry. Developing axons oftenelaborate collateral branches to allow the in-nervation of multiple synaptic targets by a sin-gle axon (O’Leary et al. 1990). During regen-eration after injury, the sprouting of branchesfrom the primary axon stumps is also believedto be important for the rewiring of nerveconnections (Hagg 2006, Schwab 2002). Al-though bifurcation of the growth cone is oneway of achieving primary branches, collat-eral branching requires the formation of newgrowth cones along the neurite shaft, followedby elongation (Figure 4). Axonal branch-ing needs to be spatiotemporally regulatedby both intrinsic and extrinsic mechanismsto ensure the proper construction of neu-ral circuits. Several extracellular factors, in-cluding some axon guidance molecules, havebeen shown to regulate axonal branching(Brose & Tessier-Lavigne 2000, Dent et al.2003). In cultured embryonic cortical neu-rons, netrin-1 elicits marked collateral axonalbranches, which depends on localized Ca2+

transients and subsequent activation of the

RyR: ryanodinereceptor

α isoform of CaMKII and mitogen-activatedprotein kinases (MAPKs) (Tang & Kalil 2005).Although the actin cytoskeleton is likely theprimary target of Ca2+ signaling, the link fromCaMKII and MAPKs to the rearrangementof the actin cytoskeleton during branching re-mains unclear (Dent & Gertler 2003, Kornack& Giger 2005).

Whereas axonal branching is mostly re-stricted to the region near target cells, den-dritic branching is much more elaborate, andits pattern largely defines the morphologi-cal phenotype of the neuron. How the in-trinsic genetic program and extrinsic factorsfrom the environment determine the forma-tion of the dendritic arbor is an outstand-ing question in neuronal cell biology ( Jan &Jan 2001). A large body of evidence supportsthe notion that Ca2+ signals generated spon-taneously or elicited by synaptic activity actthrough distinct downstream effectors, e.g.,CaMKs and MAPKs, to regulate dendriticgrowth and branching (Konur & Ghosh 2005,Lohmann & Wong 2005) (Figure 4). Two dif-ferent isoforms of CaMKII appear to mediatedifferent effects of Ca2+ on dendritic modifi-cations: α-CaMKII stabilizes or restricts den-dritic growth, whereas β-CaMKII promotesthe formation of dendritic filopodia. OtherCaMKs, especially CaMKI and CaMKIV, arealso involved in Ca2+- or activity-dependenttranscriptional and translational regulation ofdendrite development (Impey et al. 2002,Redmond et al. 2002, Wayman et al. 2006).For example, activity-dependent Ca2+ eleva-tion activates CaMKI, which phosphorylatesMAPK Ras/MEK/ERK and the transcriptionfactor CREB to enhance Wnt-2 production;this in turn promotes dendritic arborization(Wayman et al. 2006). Owing to their differ-ential Ca2+ affinities, various CaMKs may beselectively activated by Ca2+ signals of differ-ent spatiotemporal patterns, leading to dis-tinct downstream actions on various aspects ofdendrite development. Finally, localized Ca2+

signals induced by synaptic activity can regu-late local dendritic arbor growth (Van Aelst& Cline 2004) and spine dynamics (Tada &


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Sheng 2006), likely through the regulation ofactin dynamics by GTPases.

Ca2+ AND AXONREGENERATION

Injuries of the nervous system often involvetransection of nerve fibers that may causeaxon degeneration and neuronal death. Thefirst step leading to survival and regenera-tion is the resealing of the plasma membraneat the site of transection, a process depen-dent on both intra- and extracellular Ca2+

concentrations. Axotomy often causes a largeCa2+ influx into the cells, which can gener-ate detrimental cellular effects, including thedisruption of cytoskeletal architecture and in-duction of apoptosis (Coleman 2005). How-ever, the large Ca2+ influx appears to be im-portant for membrane resealing (Figure 4)because the reduction or elimination of extra-cellular Ca2+ severely delays membrane re-sealing (Rehder et al. 1992). A high-level,transient [Ca2+]i elevation to the micro- andmillimolar ranges following axotomy of cul-tured neurons is needed to trigger a cascadeof cellular events that lead to the resealing ofthe plasma membrane (Rehder et al. 1992,Xie & Barrett 1991). Two molecules down-stream of Ca2+ have been implicated in Ca2+-dependent resealing of the plasma membrane:phospholipase A2 (PLA2) and the Ca2+-sensitive protease calpain (Geddis & Rehder2003a, Gitler & Spira 1998, Xie & Barrett1991, Yawo & Kuno 1983). High [Ca2+]i acti-vates PLA2, which hydrolyzes phospholipidsto form fatty acid and lysophospholipid prod-ucts that can directly contribute to membraneresealing or indirectly activate further down-stream events. The calpain family of proteasescan be activated by micromolar-or-higher[Ca2+]i (Glading et al. 2002, Goll et al. 2003)and has been implicated in the membrane-resealing process (Gitler & Spira 1998, Xie &Barrett 1991), but the detailed mechanism forthe resealing process remains unclear. OtherCa2+-dependent cellular events, e.g., Ca2+-triggered exocytosis and the associated inser-

tion of membrane (McNeil et al. 2000), mayalso be involved in membrane resealing.

After membrane resealing, the forma-tion of new growth cones is required foraxon regeneration and rewiring of synap-tic connections. In culture following axo-tomy, new growth cones emerge only after[Ca2+]i falls back to the normal basal level,through cytoplasmic Ca2+ homeostasis mech-anisms (Geddis & Rehder 2003a). A dras-tic reduction in [Ca2+]i below the normalbasal level also delays the formation of newgrowth cones (Rehder et al. 1992), suggest-ing that an optimal range of [Ca2+]i is re-quired for growth cone formation, similar tothat found for growth cone extension. Severalenzymes have been implicated in the forma-tion of new growth cones, including PLA2,PKC, and calpain (Geddis & Rehder 2003b,Gitler & Spira 1998, Spira et al. 2001). Itis likely that mechanisms that regulate cy-toskeletal structures in growth cone initia-tion during development also operate dur-ing growth cone regeneration after axotomy(Dehmelt & Halpain 2004). Axon regenera-tion requires the resumption of the growthcapacity that was present in early develop-ment, which may require changes in geneexpression and the upregulation of growth-associated proteins, e.g., GAP43 (Bomze et al.2001, Van der Zee et al. 1989). The high ele-vation of [Ca2+]i during axotomy may serve asa trigger for changes in gene expression, in amanner analogous to the activity-dependentgene regulation that occurs under normalphysiological conditions (Hong et al. 2005,Spitzer 2006). Thus, Ca2+ signals may serveboth short- and long-term functions duringaxon regeneration—an immediate signal forregulating membrane resealing and cytoskele-tal organization—and a long-term functionin gene expression. Whereas the basal Ca2+

level may serve merely as a permissive condi-tion, Ca2+ signals may play an active role ingrowth cone regeneration (Figure 4), similarto the initiation of a new growth cone dur-ing axon branching (Tang & Kalil 2005). Fi-nally, local protein synthesis and degradation

390 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


play a role in axon regeneration (Verma et al.2005), which may be regulated by Ca2+ sig-nals (Iizuka et al. 2007, Sutton et al. 2004, Yaoet al. 2006).

Whereas extensive axon regeneration oc-curs after peripheral nerve injuries, injured ax-ons in the central nervous system (CNS) nor-mally do not regenerate. In addition to thepresence of extracellular inhibitory moleculesin the CNS that impose major obstacles to re-generation (Harel & Strittmatter 2006), adultneurons may have also lost their intrinsicgrowth capability, as suggested by the ab-sence of neurite regeneration of dissociatedadult DRG and retinal neurons in culture(Chierzi et al. 2005). Other potential intrin-sic deficiencies of adult CNS axons includepoor membrane resealing, inability to formgrowth cones, and failure of growth cone ex-tension, all of which depends on the homeo-static regulation of [Ca2+]i. Interestingly, themodulation of [Ca2+]i by electrical stimula-tion may drastically change growth cone be-havior. Ming et al. (2000) showed that incell culture, myelin-associated glycoprotein(MAG), a major inhibitor of regenerating ax-ons, causes repulsion of cultured spinal neu-rons. Interestingly, a brief train of action po-tentials can convert the response of theseneurons from repulsion to attraction. In thiscase, the Ca2+ influx resulting from elec-trical stimulation is mediated by an eleva-tion of cytosolic cAMP, presumably owingto the activation of Ca2+-dependent AC. In-terestingly, in animal models electrical stim-ulation has long been an effective means ofpromoting nerve regeneration in the injuredspinal cord, which is very likely mediated bydepolarization-induced Ca2+ signaling. Thus,a potential strategy in promoting axon regen-eration after injury is to modulate the Ca2+

homeostatic mechanisms or the effectivenessof Ca2+-activated processes so as to facili-tate membrane resealing, growth cone for-mation and extension, and the growth cone’ssensitivity to inhibitory substances in theCNS.

SYNAPTOGENESIS ANDSYNAPSE REMODELING

The establishment of synaptic connectionsinvolves motility of both the presynapticaxon and postsynaptic dendrites. In culturedhippocampal neurons, numerous filopodiaextending from dendritic shafts appear tosample their environment actively for appro-priate incoming axons. Stable contact madewith the axon, often along the axon shaft, leadsto filopodial stabilization and the subsequentdevelopment of these filopodia into dendriticspines, whereas the axonal contact sites be-come functional presynaptic boutons (Ziv &Smith 1996). Long-term imaging of nonspinydendritic arbors in the optic tectum of liv-ing zebrafish larvae also showed that nearlyall synapses form initially on newly extendeddendritic filopodia. Stable synaptic contacts inturn stabilize the filopodia, which then matureinto dendritic branches (Niell et al. 2004).

The effects of neuronal activity on synap-togenesis and connectivity are largely medi-ated by Ca2+ signals, which act either pre- orpostsynaptically to regulate the cytoskele-tal dynamics underlying the morphologicaland functional maturation of the synapse(Dillon & Goda 2005). Studies of synapto-genesis in hippocampal cultures showed thata brief period of bursting spiking of thepresynaptic neurons could promote the es-tablishment of functional synaptic transmis-sion through a Ca2+-dependent remodelingof presynaptic actin filaments (Shen et al.2006). Activity-induced Ca2+ signals may alsoexert modulatory actions at the synapse byCa2+-dependent secretion of neurotrophicsubstances, e.g., BDNF (Poo 2001). In thedeveloping optic tectum, BDNF promotessynaptogenesis by enhancing axonal and den-dritic growth (Alsina et al. 2001). Interfer-ence of BDNF signaling through its TrkB re-ceptors severely impaired the refinement ofsynaptic connections associated with the for-mation of ocular-dominance columns in thedeveloping primary visual cortex (Cabelli et al.1995).


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


LTP: long-termpotentiation

LTD: long-termdepression

Activity-dependent developmental refine-ment of neural circuits involves the establish-ment and stabilization of new synapses andthe elimination of inappropriate synapses ina manner dictated by the pattern of neuralactivity (Zhang & Poo 2002). This requiresneuronal motility associated with localizedsprouting and growth as well as the retractionof axonal and dendritic processes. The retino-tectal system of the frog and zebrafish hasbeen used extensively for studying the dynam-ics of developmental motility in vivo (Cline2001, Hua et al. 2005). In the mature nervoussystem, large-scale formation and eliminationof synaptic connections probably do not oc-cur, except under pathological conditions orfollowing denervation. Interestingly, synapseformation and elimination appear to occurthroughout life by limited dendritic spino-genesis and elimination (Grutzendler et al.2002), with synaptogenesis following spino-genesis (Knott et al. 2006). The stability ofspines depends on sensory inputs. In identi-fied somatosensory barrel cortex of the adultmouse, sensory activity is required for spineretraction (Zuo et al. 2005), a process requir-ing NMDA receptor–mediated Ca2+ influx.However, novel sensory experience inducedby trimming alternate whiskers, a paradigmthat induces adaptive functional changes inneocortical circuits, drives the stabilization ofnew spines on subclasses of cortical neurons(Holtmaat et al. 2006).

Changes in the shape and number of spineshave long been proposed as a mechanism bywhich activity induces long-term modifica-tions of synaptic efficacy. Studies of synapticplasticity in all brain regions have shownthat correlated pre- and postsynaptic activi-ties result in immediate long-term potenti-ation (LTP) or long-term depression (LTD)of synaptic efficacy, depending on the activ-ity pattern (Dan & Poo 2004, Malenka &Bear 2004). In parallel, repetitive synaptic ac-tivities also cause changes in the morphol-ogy of synapses, with a slower onset (tensof minutes), as shown by the protrusion ofnew dendritic spines, spine enlargement, and

splitting of existing spines accompanying LTP(Yuste & Bonhoeffer 2001) as well as theshrinkage or retraction of spines associatedwith LTD (Q. Zhou et al. 2004). Both thefunctional and morphological modificationsof synapses require Ca2+ signals induced bythe activation of NMDA receptors, VDCCs,or metabotropic glutamate receptors. TheseCa2+ signals activate downstream Ca2+ effec-tor enzymes, leading to changes in the num-ber and properties of postsynaptic transmit-ter receptors and/or in presynaptic efficacyin transmitter secretion (see Malenka & Bear2004). In the meantime, Ca2+ signals also trig-ger the actin cytoskeleton rearrangement inpostsynaptic spines, leading to a modificationof synaptic morphology.

Dendritic spines are highly enriched withF-actin, and rapid rearrangements of the actincytoskeleton inside the spine in response to anelevation of [Ca2+]i can change spine shapeand size to alter the efficacy of synaptic trans-mission (see Oertner & Matus 2005). Theactin cytoskeleton also anchors postsynap-tic glutamate receptors, and its modulationaffects the endocytic removal or membraneinsertion of glutamate receptors, leading tofunctional synaptic modification. This is illus-trated by the findings that glutamate-inducedinternalization of synaptic AMPA receptorsin cultured neurons requires a rise in post-synaptic Ca2+ and that the internalizationis mimicked by latrunculin A, which selec-tively depolymerizes F-actin, and blocked byjasplakinolide, which stabilizes F-actin fila-ments (Zhou et al. 2001). Exactly how Ca2+

signals regulate the actin cytoskeleton maybe revealed by the spatiotemporal pattern ofthe Ca2+ signal triggered by neuronal activ-ity. Korkotian & Segal (2001) showed thatbursts of action potentials in the postsynap-tic neuron cause a momentary contraction ofdendritic spines that are blocked by latrun-culin B inhibition of actin polymerization.Low-frequency stimulation, in contrast, sta-bilizes the dynamic actin in the spine of cul-tured neurons via the Ca2+-dependent actin-binding protein gelsolin (Star et al. 2002).

392 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Postsynaptic NMDA receptor activation leadsto the targeting of profilin, a regulator ofactin polymerization, to spine heads, pre-vents actin-based changes in spine shape, andstabilizes synaptic structure (Ackermann &Matus 2003). There also appear to be di-vergent Ca2+-dependent pathways leading tofunctional and structural modifications at thesynapse. For example, both the shrinkage ofspines and LTD require the activation ofNMDA receptors and calcineurin. However,spine shrinkage is mediated by cofilin butnot by protein phosphatase 1 (PP1), which isessential for LTD, suggesting that differentdownstream pathways are involved in spineshrinkage and LTD (F.Q. Zhou et al. 2004).The small GTPases Rac and Rho play acritical role in the maintenance of dendriticspines and branches in cultured hippocam-pal pyramidal neurons (Nakayama & Luo2000, Nakayama et al. 2000). Because theseGTPases are downstream effectors of Ca2+,they may also mediate the action of Ca2+ onspine motility.

The presynaptic terminals and postsynap-tic spines contain cytoskeletal elements simi-lar to that of the growth cone filopodia. Unlikethe growth cone, the assembly/disassembly ofcytoskeletal filaments and endo-/exocytic ac-tivities are in a state of dynamic equilibriumat the synapse, maintaining its structural sta-bility. However, activity-dependent Ca2+ sig-nals in the pre- or postsynaptic cell may tipthe balance by inducing a net insertion or re-moval of plasma membrane components, re-sulting in an addition or a reduction of trans-mitter receptors and ion channels as well asthe growth or retraction of pre- and post-synaptic elements. Thus, Ca2+ signals thatserve to regulate the growth and pathfind-

ing of growth cones early in development ap-pear to be redeployed in regulating fine-scaleneuronal motility at the synapse. The bidi-rectional cellular responses triggered by Ca2+

signals further exemplify the parallels betweenthe growth cone and the synapse: Attractiveversus repulsive turning of growth cones trig-gered by high- versus low-level Ca2+ gradi-ents across the growth cone is analogous tothe bidirectional synaptic modification (LTPor LTD, or spine growth or retraction) trig-gered by high- versus low-level postsynapticCa2+ rises in response to synaptic activity, me-diated by overlapping sets of Ca2+-dependentkinases and phosphatases (Gomez & Zheng2006, Henley & Poo 2004, Malenka & Bear2004, Wen & Zheng 2006).

CONCLUSION

As the primary link between electrical activ-ity and biochemical events, Ca2+ signalingplays a central role in multiple cellular ac-tions, including the regulation of neuronalmotility. Much is known at present for po-tential pathways that may rapidly transduceCa2+ signals to changes in cytoskeletal dy-namics. However, how a myriad of otherdownstream actions of Ca2+ signals, includingCa2+-dependent transcriptional and transla-tional events, influence neuronal motility overa longer duration remains largely unclear.Furthermore, given that the information inthe nervous system is often coded in the pat-tern of electrical activity, how Ca2+ signalsconvey and convert different patterns of elec-trical activity into distinct biochemical eventsto properly modulate neuronal functions, in-cluding various forms of motility, remains anoutstanding issue in cellular neurobiology.

SUMMARY POINTS

1. Ca2+ signals regulate a variety of neuronal motility activities underlying the formation,refinement, and maintenance of neuronal circuitry.

2. Intracellular Ca2+ signals of different spatiotemporal patterns act through distinctsignal transduction pathways to regulate specific motility-associated activities.


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


3. Most of the Ca2+ downstream effectors and transduction mechanisms are redeployedbut adjusted to perform specific tasks of motility regulation at different stages of neuraldevelopment.

4. The membrane, cytoskeleton, and adhesion are the primary targets of Ca2+ signalingcascades for controlling and regulating various aspects of neuronal motility.

FUTURE ISSUES

1. The intricate cross talk between Ca2+ and other signaling pathways that regulateneuronal motility needs to be clarified further.

2. The spatiotemporal properties of the Ca2+ signals that control and regulate distinctaspects of neuronal motility require further elucidation.

3. There is a need for improvement in the methods for in vivo imaging studies ofCa2+ signaling in various forms of motility essential for various stages of neuraldevelopment.

4. Evaluation and investigation of the functional roles of various types of Ca2+ signalsin neural development in vivo are much needed.

5. There is a need for the development of therapeutic strategies targeting the Ca2+

pathway for promoting regeneration after injury and for treatments of neurologicaldiseases resulting from abnormal neuronal motility.

DISCLOSURE STATEMENT

The authors do not have any biases that might be perceived as affecting the objectivity of thisreview.

ACKNOWLEDGMENTS

The authors would like to thank members of their laboratories for their contribution to theresearch. Work on neuronal motility in the authors’ laboratories was supported by grants fromthe National Institutes of Health (NS036241 to JQZ and NS22764 to MMP).

LITERATURE CITED

Ackermann M, Matus A. 2003. Activity-induced targeting of profilin and stabilization of den-dritic spine morphology. Nat. Neurosci. 6:1194–200

Agnew BJ, Minamide LS, Bamburg JR. 1995. Reactivation of phosphorylated actin depoly-merizing factor and identification of the regulatory site. J. Biol. Chem. 270:17582–87

Aizawa H, Wakatsuki S, Ishii A, Moriyama K, Sasaki Y, et al. 2001. Phosphorylation of cofilin byLIM-kinase is necessary for semaphorin 3A-induced growth cone collapse. Nat. Neurosci.4:367–73

al-Baldawi NF, Abercrombie RF. 1995. Calcium diffusion coefficient in Myxicola axoplasm.Cell Calcium 17:422–30

394 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Alsina B, Vu T, Cohen-Cory S. 2001. Visualizing synapse formation in arborizing optic axonsin vivo: dynamics and modulation by BDNF. Nat. Neurosci. 4:1093–101

Aspenstrom P. 2004. Integration of signalling pathways regulated by small GTPases and cal-cium. Biochim. Biophys. Acta 1742:51–58

Ayala R, Shu T, Tsai LH. 2007. Trekking across the brain: the journey of neuronal migration.Cell 128:29–43

Baimbridge KG, Celio MR, Rogers JH. 1992. Calcium-binding proteins in the nervous system.Trends Neurosci. 15:303–8

Bamburg JR, Bray D. 1987. Distribution and cellular localization of actin depolymerizingfactor. J. Cell Biol. 105:2817–25

Behar TN, Li YX, Tran HT, Ma W, Dunlap V, et al. 1996. GABA stimulates chemotaxisand chemokinesis of embryonic cortical neurons via calcium-dependent mechanisms. J.Neurosci. 16:1808–18

Behar TN, Schaffner AE, Scott CA, Greene CL, Barker JL. 2000. GABA receptor antagonistsmodulate postmitotic cell migration in slice cultures of embryonic rat cortex. Cereb. Cortex10:899–909

Ben-Ari Y. 2002. Excitatory actions of gaba during development: the nature of the nurture.Nat. Rev. Neurosci. 3:728–39

Berlin JR, Bassani JW, Bers DM. 1994. Intrinsic cytosolic calcium buffering properties of singlerat cardiac myocytes. Biophys. J. 67:1775–87

Berridge MJ, Bootman MD, Roderick HL. 2003. Calcium signalling: dynamics, homeostasisand remodelling. Nat. Rev. Mol. Cell Biol. 4:517–29

Berridge MJ, Lipp P, Bootman MD. 2000. The versatility and universality of calcium signalling.Nat. Rev. Mol. Cell Biol. 1:11–21

Blaser H, Reichman-Fried M, Castanon I, Dumstrei K, Marlow FL, et al. 2006. Migration ofzebrafish primordial germ cells: a role for myosin contraction and cytoplasmic flow. Dev.Cell 11:613–27

Blaustein MP. 1988. Calcium transport and buffering in neurons. Trends Neurosci. 11:438–43Blaustein MP, Goldman WF, Fontana G, Krueger BK, Santiago EM, et al. 1991. Physiological

roles of the sodium-calcium exchanger in nerve and muscle. Ann. N.Y. Acad. Sci. 639:254–74

Bomze HM, Bulsara KR, Iskandar BJ, Caroni P, Skene JH. 2001. Spinal axon regenerationevoked by replacing two growth cone proteins in adult neurons. Nat. Neurosci. 4:38–43

Bonhoeffer T, Yuste R. 2002. Spine motility. Phenomenology, mechanisms, and function.Neuron 35:1019–27

Brocke L, Chiang LW, Wagner PD, Schulman H. 1999. Functional implications of the subunitcomposition of neuronal CaM kinase II. J. Biol. Chem. 274:22713–22

Bronner-Fraser M. 1994. Neural crest cell formation and migration in the developing embryo.FASEB J. 8:699–706

Brose K, Tessier-Lavigne M. 2000. Slit proteins: key regulators of axon guidance, axonalbranching, and cell migration. Curr. Opin. Neurobiol. 10:95–102

Brundage RA, Fogarty KE, Tuft RA, Fay FS. 1991. Calcium gradients underlying polarizationand chemotaxis of eosinophils. Science 254:703–6

Buck KB, Zheng JQ. 2002. Growth cone turning induced by direct local modification ofmicrotubule dynamics. J. Neurosci. 22:9358–67

Cabelli RJ, Hohn A, Shatz CJ. 1995. Inhibition of ocular dominance column formation byinfusion of NT-4/5 or BDNF. Science 267:1662–66


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Carlier MF, Laurent V, Santolini J, Melki R, Didry D, et al. 1997. Actin depolymerizing factor(ADF/cofilin) enhances the rate of filament turnover: implication in actin-based motility.J. Cell Biol. 136:1307–22

Chierzi S, Ratto GM, Verma P, Fawcett JW. 2005. The ability of axons to regenerate theirgrowth cones depends on axonal type and age, and is regulated by calcium, cAMP andERK. Eur J. Neurosci. 21:2051–62

Chin D, Means AR. 2000. Calmodulin: a prototypical calcium sensor. Trends Cell Biol. 10:322–28

Clapham DE. 1995. Calcium signaling. Cell 80:259–68Clapham DE, Runnels LW, Strubing C. 2001. The TRP ion channel family. Nat. Rev. Neurosci.

2:387–96Cline HT. 2001. Dendritic arbor development and synaptogenesis. Curr. Opin. Neurobiol.

11:118–26Coleman M. 2005. Axon degeneration mechanisms: commonality amid diversity. Nat. Rev.

Neurosci. 6:889–98Cooper DM. 2005. Compartmentalization of adenylate cyclase and cAMP signalling. Biochem.

Soc. Trans. 33:1319–22Cooper DM, Mons N, Karpen JW. 1995. Adenylyl cyclases and the interaction between calcium

and cAMP signalling. Nature 374:421–24Corbin JG, Nery S, Fishell G. 2001. Telencephalic cells take a tangent: nonradial migration in

the mammalian forebrain. Nat. Neurosci. 4(Suppl.):1177–82Crivici A, Ikura M. 1995. Molecular and structural basis of target recognition by calmodulin.

Annu. Rev. Biophys. Biomol. Struct. 24:85–116Dan Y, Poo MM. 2004. Spike timing-dependent plasticity of neural circuits. Neuron 44:23–30Dawson TM, Sasaki M, Gonzalez-Zulueta M, Dawson VL. 1998. Regulation of neuronal nitric

oxide synthase and identification of novel nitric oxide signaling pathways. Prog. Brain Res.118:3–11

Dawson TM, Snyder SH. 1994. Gases as biological messengers: nitric oxide and carbon monox-ide in the brain. J. Neurosci. 14:5147–59

Dehmelt L, Halpain S. 2004. Actin and microtubules in neurite initiation: Are MAPs themissing link? J. Neurobiol. 58:18–33

Dent EW, Gertler FB. 2003. Cytoskeletal dynamics and transport in growth cone motility andaxon guidance. Neuron 40:209–27

Dent EW, Tang F, Kalil K. 2003. Axon guidance by growth cones and branches: commoncytoskeletal and signaling mechanisms. Neuroscientist 9:343–53

Dickson BJ. 2001. Rho GTPases in growth cone guidance. Curr. Opin. Neurobiol. 11:103–10Dickson BJ. 2002. Molecular mechanisms of axon guidance. Science 298:1959–64Dillon C, Goda Y. 2005. The actin cytoskeleton: integrating form and function at the synapse.

Annu. Rev. Neurosci. 28:25–55Ernst AF, Gallo G, Letourneau PC, McLoon SC. 2000. Stabilization of growing retinal ax-

ons by the combined signaling of nitric oxide and brain-derived neurotrophic factor. J.Neurosci. 20:1458–69

Ezratty EJ, Partridge MA, Gundersen GG. 2005. Microtubule-induced focal adhesion disas-sembly is mediated by dynamin and focal adhesion kinase. Nat. Cell Biol. 7:581–90

Fay FS, Gilbert SH, Brundage RA. 1995. Calcium signalling during chemotaxis. Ciba Found.Symp. 188:121–35; discussion 36–40

Fink CC, Bayer KU, Myers JW, Ferrell JE Jr, Schulman H, Meyer T. 2003. Selective regulationof neurite extension and synapse formation by the beta but not the alpha isoform ofCaMKII. Neuron 39:283–97

396 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Fleming IN, Elliott CM, Buchanan FG, Downes CP, Exton JH. 1999. Ca2+/calmodulin-dependent protein kinase II regulates Tiam1 by reversible protein phosphorylation. J.Biol. Chem. 274:12753–58

Forscher P, Smith SJ. 1988. Actions of cytochalasins on the organization of actin filaments andmicrotubules in a neuronal growth cone. J. Cell Biol. 107:1505–16

Fukata M, Nakagawa M, Kaibuchi K. 2003. Roles of Rho-family GTPases in cell polarisationand directional migration. Curr. Opin. Cell Biol. 15:590–97

Fukata M, Watanabe T, Noritake J, Nakagawa M, Yamaga M, et al. 2002. Rac1 and Cdc42capture microtubules through IQGAP1 and CLIP-170. Cell 109:873–85

Gallo G, Yee HF Jr, Letourneau PC. 2002. Actin turnover is required to prevent axon retractiondriven by endogenous actomyosin contractility. J. Cell Biol. 158:1219–28

Gan WB. 2003. Glutamate-dependent stabilization of presynaptic terminals. Neuron 38:677–78Ganguly K, Schinder AF, Wong ST, Poo M. 2001. GABA itself promotes the developmental

switch of neuronal GABAergic responses from excitation to inhibition. Cell 105:521–32Garcia ML, Strehler EE. 1999. Plasma membrane calcium ATPases as critical regulators of

calcium homeostasis during neuronal cell function. Front. Biosci. 4:D869–82Geddis MS, Rehder V. 2003a. Initial stages of neural regeneration in Helisoma trivolvis are

dependent upon PLA2 activity. J. Neurobiol. 54:555–65Geddis MS, Rehder V. 2003b. The phosphorylation state of neuronal processes determines

growth cone formation after neuronal injury. J. Neurosci. Res. 74:210–20Gilbert SH, Perry K, Fay FS. 1994. Mediation of chemoattractant-induced changes in [Ca2+]i

and cell shape, polarity, and locomotion by InsP3, DAG, and protein kinase C in newteosinophils. J. Cell Biol. 127:489–503

Gitler D, Spira ME. 1998. Real time imaging of calcium-induced localized proteolytic activityafter axotomy and its relation to growth cone formation. Neuron 20:1123–35

Glading A, Lauffenburger DA, Wells A. 2002. Cutting to the chase: calpain proteases in cellmotility. Trends Cell Biol. 12:46–54

Goll DE, Thompson VF, Li H, Wei W, Cong J. 2003. The calpain system. Physiol. Rev.83:731–801

Gomez TM, Spitzer NC. 2000. Regulation of growth cone behavior by calcium: new dynamicsto earlier perspectives. J. Neurobiol. 44:174–83

Gomez TM, Zheng JQ. 2006. The molecular basis for calcium-dependent axon pathfinding.Nat. Rev. Neurosci. 7:115–25

Gorbunova YV, Spitzer NC. 2002. Dynamic interactions of cyclic AMP transients and spon-taneous Ca2+ spikes. Nature 418:93–96

Goto S, Yamamoto H, Fukunaga K, Iwasa T, Matsukado Y, Miyamoto E. 1985. Dephospho-rylation of microtubule-associated protein 2, tau factor, and tubulin by calcineurin. J.Neurochem. 45:276–83

Grabarek Z. 2006. Structural basis for diversity of the EF-hand calcium-binding proteins. J.Mol. Biol. 359:509–25

Graef IA, Wang F, Charron F, Chen L, Neilson J, et al. 2003. Neurotrophins and netrins requirecalcineurin/NFAT signaling to stimulate outgrowth of embryonic axons. Cell 113:657–70

Griffith LC. 2004. Calcium/calmodulin-dependent protein kinase II: an unforgettable kinase.J. Neurosci. 24:8391–93

Grutzendler J, Kasthuri N, Gan WB. 2002. Long-term dendritic spine stability in the adultcortex. Nature 420:812–16

Guan CB, Xu HT, Jin M, Yuan XB, Poo MM. 2007. Long-range Ca2+ signaling from growthcone to soma mediates reversal of neuronal migration induced by Slit-2. Cell 129:385–95


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Haase A, Bicker G. 2003. Nitric oxide and cyclic nucleotides are regulators of neuronal migra-tion in an insect embryo. Development 130:3977–87

Hagg T. 2006. Collateral sprouting as a target for improved function after spinal cord injury.J. Neurotrauma 23:281–94

Hanson PI, Schulman H. 1992. Neuronal Ca2+/calmodulin-dependent protein kinases. Annu.Rev. Biochem. 61:559–601

Harel NY, Strittmatter SM. 2006. Can regenerating axons recapitulate developmental guidanceduring recovery from spinal cord injury? Nat. Rev. Neurosci. 7:603–16

Hatten ME. 1999. Central nervous system neuronal migration. Annu. Rev. Neurosci. 22:511–39Helmchen F, Imoto K, Sakmann B. 1996. Ca2+ buffering and action potential-evoked Ca2+

signaling in dendrites of pyramidal neurons. Biophys. J. 70:1069–81Henley J, Poo MM. 2004. Guiding neuronal growth cones using Ca2+ signals. Trends Cell Biol.

14:320–30Henley JR, Huang KH, Wang D, Poo MM. 2004. Calcium mediates bidirectional growth cone

turning induced by myelin-associated glycoprotein. Neuron 44:909–16Henschler R, Piiper A, Bistrian R, Mobest D. 2003. SDF-1α-induced intracellular calcium

transient involves Rho GTPase signalling and is required for migration of hematopoieticprogenitor cells. Biochem. Biophys. Res. Commun. 311:1067–71

Hirasawa M, Ohshima T, Takahashi S, Longenecker G, Honjo Y, et al. 2004. Perinatal abro-gation of Cdk5 expression in brain results in neuronal migration defects. Proc. Natl. Acad.Sci. USA 101:6249–54

Hoeflich KP, Ikura M. 2002. Calmodulin in action: diversity in target recognition and activationmechanisms. Cell 108:739–42

Holtmaat A, Wilbrecht L, Knott GW, Welker E, Svoboda K. 2006. Experience-dependentand cell-type-specific spine growth in the neocortex. Nature 441:979–83

Hong EJ, West AE, Greenberg ME. 2005. Transcriptional control of cognitive development.Curr. Opin. Neurobiol. 15:21–28

Horwitz AR, Parsons JT. 1999. Cell migration—movin’ on. Science 286:1102–3Hsieh SH, Ferraro GB, Fournier AE. 2006. Myelin-associated inhibitors regulate cofilin phos-

phorylation and neuronal inhibition through LIM kinase and Slingshot phosphatase. J.Neurosci. 26:1006–15

Hua JY, Smear MC, Baier H, Smith SJ. 2005. Regulation of axon growth in vivo by activity-based competition. Nature 434:1022–26

Huang TY, DerMardirossian C, Bokoch GM. 2006. Cofilin phosphatases and regulation ofactin dynamics. Curr. Opin. Cell Biol. 18:26–31

Hudmon A, Schulman H. 2002. Neuronal Ca2+/calmodulin-dependent protein kinase II: therole of structure and autoregulation in cellular function. Annu. Rev. Biochem. 71:473–510

Iizuka A, Sengoku K, Iketani M, Nakamura F, Sato Y, et al. 2007. Calcium-induced synergisticinhibition of a translational factor eEF2 in nerve growth cones. Biochem. Biophys. Res.Commun. 353:244–50

Impey S, Fong AL, Wang Y, Cardinaux JR, Fass DM, et al. 2002. Phosphorylation of CBPmediates transcriptional activation by neural activity and CaM kinase IV. Neuron 34:235–44

Jan YN, Jan LY. 2001. Dendrites. Genes Dev. 15:2627–41Jan YN, Jan LY. 2003. The control of dendrite development. Neuron 40:229–42Jin M, Guan CB, Jiang YA, Chen G, Zhao CT, et al. 2005. Ca2+-dependent regulation of Rho

GTPases triggers turning of nerve growth cones. J. Neurosci. 25:2338–47Jontes JD, Smith SJ. 2000. Filopodia, spines, and the generation of synaptic diversity. Neuron

27:11–14

398 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Kalil K, Dent EW. 2005. Touch and go: Guidance cues signal to the growth cone cytoskeleton.Curr. Opin. Neurobiol. 15:521–26

Kater SB, Mattson MP, Cohan C, Connor J. 1988. Calcium regulation of the neuronal growthcone. Trends Neurosci. 11:315–21

Kawauchi T, Chihama K, Nabeshima Y, Hoshino M. 2006. Cdk5 phosphorylates and stabilizesp27kip1 contributing to actin organization and cortical neuronal migration. Nat. Cell Biol.8:17–26

Kholmanskikh SS, Koeller HB, Wynshaw-Boris A, Gomez T, Letourneau PC, Ross ME. 2006.Calcium-dependent interaction of Lis1 with IQGAP1 and Cdc42 promotes neuronalmotility. Nat. Neurosci. 9:50–57

Kim Y, Sung JY, Ceglia I, Lee KW, Ahn JH, et al. 2006. Phosphorylation of WAVE1 regulatesactin polymerization and dendritic spine morphology. Nature 442:814–17

Knott GW, Holtmaat A, Wilbrecht L, Welker E, Svoboda K. 2006. Spine growth precedessynapse formation in the adult neocortex in vivo. Nat. Neurosci. 9:1117–24

Komuro H, Kumada T. 2005. Ca2+ transients control CNS neuronal migration. Cell Calcium37:387–93

Komuro H, Rakic P. 1992. Selective role of N-type calcium channels in neuronal migration.Science 257:806–9

Komuro H, Rakic P. 1993. Modulation of neuronal migration by NMDA receptors. Science260:95–97

Komuro H, Rakic P. 1996. Intracellular Ca2+ fluctuations modulate the rate of neuronal mi-gration. Neuron 17:275–85

Konur S, Ghosh A. 2005. Calcium signaling and the control of dendritic development. Neuron46:401–5

Korey CA, Van Vactor D. 2000. From the growth cone surface to the cytoskeleton: one journey,many paths. J. Neurobiol. 44:184–93

Korkotian E, Segal M. 2001. Spike-associated fast contraction of dendritic spines in culturedhippocampal neurons. Neuron 30:751–58

Kornack DR, Giger RJ. 2005. Probing microtubule +TIPs: regulation of axon branching. Curr.Opin. Neurobiol. 15:58–66

Kriegstein AR, Noctor SC. 2004. Patterns of neuronal migration in the embryonic cortex.Trends Neurosci. 27:392–99

Kuhn TB, Meberg PJ, Brown MD, Bernstein BW, Minamide LS, et al. 2000. Regulating actindynamics in neuronal growth cones by ADF/cofilin and Rho family GTPases. J. Neurobiol.44:126–44

Kumada T, Komuro H. 2004. Completion of neuronal migration regulated by loss of Ca2+

transients. Proc. Natl. Acad. Sci. USA 101:8479–84Laffafian I, Hallett MB. 1995. Does cytosolic free Ca2+ signal neutrophil chemotaxis in response

to formylated chemotactic peptide? J. Cell Sci. 108(Pt. 10):3199–205Lautermilch NJ, Spitzer NC. 2000. Regulation of calcineurin by growth cone calcium waves

controls neurite extension. J. Neurosci. 20:315–25Lee H, Engel U, Rusch J, Scherrer S, Sheard K, Van Vactor D. 2004. The microtubule plus

end tracking protein Orbit/MAST/CLASP acts downstream of the tyrosine kinase Abl inmediating axon guidance. Neuron 42:913–26

Lee J, Ishihara A, Oxford G, Johnson B, Jacobson K. 1999. Regulation of cell movement ismediated by stretch-activated calcium channels. Nature 400:382–86

Li HS, Xu XZ, Montell C. 1999. Activation of a TRPC3-dependent cation current throughthe neurotrophin BDNF. Neuron 24:261–73


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Lohmann C, Wong RO. 2005. Regulation of dendritic growth and plasticity by local and globalcalcium dynamics. Cell Calcium 37:403–9

Lu M, Witke W, Kwiatkowski DJ, Kosik KS. 1997. Delayed retraction of filopodia in gelsolinnull mice. J. Cell Biol. 138:1279–87

Luo L. 2000. Rho GTPases in neuronal morphogenesis. Nat. Rev. Neurosci. 1:173–80Maciver SK. 1998. How ADF/cofilin depolymerizes actin filaments. Curr. Opin. Cell Biol.

10:140–44Malenka RC, Bear MF. 2004. LTP and LTD: an embarrassment of riches. Neuron 44:5–21Mandelkow EM, Biernat J, Drewes G, Gustke N, Trinczek B, Mandelkow E. 1995. Tau do-

mains, phosphorylation, and interactions with microtubules. Neurobiol. Aging 16:355–62;discussion 62–63

Maricich SM, Gilmore EC, Herrup K. 2001. The role of tangential migration in the estab-lishment of mammalian cortex. Neuron 31:175–78

Marin O, Rubenstein JL. 2001. A long, remarkable journey: tangential migration in the telen-cephalon. Nat. Rev. Neurosci. 2:780–90

McNeil PL, Vogel SS, Miyake K, Terasaki M. 2000. Patching plasma membrane disruptionswith cytoplasmic membrane. J. Cell Sci. 113(Pt. 11):1891–902

Meberg PJ, Ono S, Minamide LS, Takahashi M, Bamburg JR. 1998. Actin depolymerizingfactor and cofilin phosphorylation dynamics: response to signals that regulate neuriteextension. Cell Motil. Cytoskelet. 39:172–90

Medeiros NA, Burnette DT, Forscher P. 2006. Myosin II functions in actin-bundle turnoverin neuronal growth cones. Nat. Cell Biol. 8:215–26

Meyer G, Feldman EL. 2002. Signaling mechanisms that regulate actin-based motility pro-cesses in the nervous system. J. Neurochem. 83:490–503

Ming G, Henley J, Tessier-Lavigne M, Song H, Poo M. 2001. Electrical activity modulatesgrowth cone guidance by diffusible factors. Neuron 29:441–52

Miyawaki A. 2003. Fluorescence imaging of physiological activity in complex systems usingGFP-based probes. Curr. Opin. Neurobiol. 13:591–96

Miyawaki A, Llopis J, Heim R, McCaffery JM, Adams JA, et al. 1997. Fluorescent indicatorsfor Ca2+ based on green fluorescent proteins and calmodulin. Nature 388:882–87

Moya F, Valdeolmillos M. 2004. Polarized increase of calcium and nucleokinesis in tangentiallymigrating neurons. Cereb. Cortex 14:610–18

Murthy VN, Sejnowski TJ, Stevens CF. 2000. Dynamics of dendritic calcium transients evokedby quantal release at excitatory hippocampal synapses. Proc. Natl. Acad. Sci. USA 97:901–6

Nakatani K, Chen C, Yau KW, Koutalos Y. 2002. Calcium and phototransduction. Adv. Exp.Med. Biol. 514:1–20

Nakayama AY, Harms MB, Luo L. 2000. Small GTPases Rac and Rho in the maintenance ofdendritic spines and branches in hippocampal pyramidal neurons. J. Neurosci. 20:5329–38

Nakayama AY, Luo L. 2000. Intracellular signaling pathways that regulate dendritic spinemorphogenesis. Hippocampus 10:582–86

Niell CM, Meyer MP, Smith SJ. 2004. In vivo imaging of synapse formation on a growingdendritic arbor. Nat. Neurosci. 7:254–60

Niwa R, Nagata-Ohashi K, Takeichi M, Mizuno K, Uemura T. 2002. Control of actin reor-ganization by Slingshot, a family of phosphatases that dephosphorylate ADF/cofilin. Cell108:233–46

Nobes CD, Hall A. 1995. Rho, Rac, and Cdc42 GTPases regulate the assembly of multimolec-ular focal complexes associated with actin stress fibers, lamellipodia, and filopodia. Cell81:53–62

400 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


O’Leary DD, Bicknese AR, De Carlos JA, Heffner CD, Koester SE, et al. 1990. Target selectionby cortical axons: alternative mechanisms to establish axonal connections in the developingbrain. Cold Spring Harb. Symp. Quant. Biol. 55:453–68

Oertner TG, Matus A. 2005. Calcium regulation of actin dynamics in dendritic spines. CellCalcium 37:477–82

Ooashi N, Futatsugi A, Yoshihara F, Mikoshiba K, Kamiguchi H. 2005. Cell adhesion moleculesregulate Ca2+-mediated steering of growth cones via cyclic AMP and ryanodine receptortype 3. J. Cell Biol. 170:1159–67

Panicker AK, Buhusi M, Erickson A, Maness PF. 2006. Endocytosis of beta1 integrins isan early event in migration promoted by the cell adhesion molecule L1. Exp. Cell Res.312:299–307

Parekh AB, Putney JW Jr. 2005. Store-operated calcium channels. Physiol. Rev. 85:757–810Park HT, Wu J, Rao Y. 2002. Molecular control of neuronal migration. Bioessays 24:821–27Piper M, Anderson R, Dwivedy A, Weinl C, van Horck F, et al. 2006. Signaling mechanisms

underlying Slit2-induced collapse of Xenopus retinal growth cones. Neuron 49:215–28Pollard TD, Blanchoin L, Mullins RD. 2000. Molecular mechanisms controlling actin filament

dynamics in nonmuscle cells. Annu. Rev. Biophys. Biomol. Struct. 29:545–76Poo MM. 2001. Neurotrophins as synaptic modulators. Nat. Rev. Neurosci. 2:24–32Price LS, Langeslag M, ten Klooster JP, Hordijk PL, Jalink K, Collard JG. 2003. Calcium

signaling regulates translocation and activation of Rac. J. Biol. Chem. 278:39413–21Rakic P. 1995. Radial versus tangential migration of neuronal clones in the developing cerebral

cortex. Proc. Natl. Acad. Sci. USA 92:11323–27Ramon y Cajal S. 1890. Sur l’origine et les ramifications des fibres nerveuses de la moelle

embryonaire. Anat. Anz. 5:609–13Redmond L, Kashani AH, Ghosh A. 2002. Calcium regulation of dendritic growth via CaM

kinase IV and CREB-mediated transcription. Neuron 34:999–1010Rehder V, Jensen JR, Kater SB. 1992. The initial stages of neural regeneration are dependent

upon intracellular calcium levels. Neuroscience 51:565–74Renteria RC, Constantine-Paton M. 1996. Exogenous nitric oxide causes collapse of retinal

ganglion cell axonal growth cones in vitro. J. Neurobiol. 29:415–28Rivera C, Voipio J, Payne JA, Ruusuvuori E, Lahtinen H, et al. 1999. The K+/Cl− cotransporter

KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397:251–55Robles E, Huttenlocher A, Gomez TM. 2003. Filopodial calcium transients regulate growth

cone motility and guidance through local activation of calpain. Neuron 38:597–609Rodriguez OC, Schaefer AW, Mandato CA, Forscher P, Bement WM, Waterman-Storer CM.

2003. Conserved microtubule-actin interactions in cell movement and morphogenesis.Nat. Cell Biol. 5:599–609

Ruchhoeft ML, Harris WA. 1997. Myosin functions in Xenopus retinal ganglion cell growthcone motility in vivo. J. Neurobiol. 32:567–78

Schmidt JT, Morgan P, Dowell N, Leu B. 2002. Myosin light chain phosphorylation andgrowth cone motility. J. Neurobiol. 52:175–88

Schwab ME. 2002. Increasing plasticity and functional recovery of the lesioned spinal cord.Prog. Brain Res. 137:351–59

Segal M. 2005. Dendritic spines and long-term plasticity. Nat. Rev. Neurosci. 6:277–84Sheetz MP, Felsenfeld DP, Galbraith CG. 1998. Cell migration: regulation of force on

extracellular-matrix-integrin complexes. Trends Cell Biol. 8:51–54Shen W, Wu B, Zhang Z, Dou Y, Rao ZR, et al. 2006. Activity-induced rapid synaptic matu-

ration mediated by presynaptic Cdc42 signaling. Neuron 50:401–14


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Soboloff J, Spassova MA, Dziadek MA, Gill DL. 2006. Calcium signals mediated by STIMand Orai proteins: a new paradigm in interorganelle communication. Biochim. Biophys.Acta 1763:1161–68

Spira ME, Oren R, Dormann A, Ilouz N, Lev S. 2001. Calcium, protease activation, andcytoskeleton remodeling underlie growth cone formation and neuronal regeneration. CellMol. Neurobiol. 21:591–604

Spitzer NC. 2006. Electrical activity in early neuronal development. Nature 444:707–12Star EN, Kwiatkowski DJ, Murthy VN. 2002. Rapid turnover of actin in dendritic spines and

its regulation by activity. Nat. Neurosci. 5:239–46Sutton MA, Wall NR, Aakalu GN, Schuman EM. 2004. Regulation of dendritic protein syn-

thesis by miniature synaptic events. Science 304:1979–83Tada T, Sheng M. 2006. Molecular mechanisms of dendritic spine morphogenesis. Curr. Opin.

Neurobiol. 16:95–101Tam T, Mathews E, Snutch TP, Schafer WR. 2000. Voltage-gated calcium channels direct

neuronal migration in Caenorhabditis elegans. Dev. Biol. 226:104–17Tang F, Kalil K. 2005. Netrin-1 induces axon branching in developing cortical neurons by

frequency-dependent calcium signaling pathways. J. Neurosci. 25:6702–15Tessier-Lavigne M, Goodman CS. 1996. The molecular biology of axon guidance. Science

274:1123–33Toba Y, Pakiam JG, Wray S. 2005. Voltage-gated calcium channels in developing GnRH-1

neuronal system in the mouse. Eur. J. Neurosci. 22:79–92Tojima T, Akiyama H, Itofusa R, Li Y, Katayama H, et al. 2007. Attractive axon guidance

involves asymmetric membrane transport and exocytosis in the growth cone. Nat. Neurosci.10:58–66

Tombes RM, Faison MO, Turbeville JM. 2003. Organization and evolution of multifunctionalCa2+/CaM-dependent protein kinase genes. Gene 322:17–31

Trimm KR, Rehder V. 2004. Nitric oxide acts as a slow-down and search signal in developingneurites. Eur. J. Neurosci. 19:809–18

Tsien RY. 1980. New calcium indicators and buffers with high selectivity against magne-sium and protons: design, synthesis, and properties of prototype structures. Biochemistry19:2396–404

Turney SG, Bridgman PC. 2005. Laminin stimulates and guides axonal outgrowth via growthcone myosin II activity. Nat. Neurosci. 8:717–19

Van Aelst L, Cline HT. 2004. Rho GTPases and activity-dependent dendrite development.Curr. Opin. Neurobiol. 14:297–304

Van der Zee CE, Nielander HB, Vos JP, Lopes da Silva S, Verhaagen J, et al. 1989. Expressionof growth-associated protein B-50 (GAP43) in dorsal root ganglia and sciatic nerve duringregenerative sprouting. J. Neurosci. 9:3505–12

Verma P, Chierzi S, Codd AM, Campbell DS, Meyer RL, et al. 2005. Axonal protein synthesisand degradation are necessary for efficient growth cone regeneration. J. Neurosci. 25:331–42

Wayman GA, Impey S, Marks D, Saneyoshi T, Grant WF, et al. 2006. Activity-dependent den-dritic arborization mediated by CaM-kinase I activation and enhanced CREB-dependenttranscription of Wnt-2. Neuron 50:897–909

Wayman GA, Kaech S, Grant WF, Davare M, Impey S, et al. 2004. Regulation of axonalextension and growth cone motility by calmodulin-dependent protein kinase I. J. Neurosci.24:3786–94

402 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Wei FY, Tomizawa K, Ohshima T, Asada A, Saito T, et al. 2005. Control of cyclin-dependentkinase 5 (Cdk5) activity by glutamatergic regulation of p35 stability. J. Neurochem. 93:502–12

Wen Z, Guirland C, Ming GL, Zheng JQ. 2004. A CaMKII/calcineurin switch controls thedirection of Ca2+-dependent growth cone guidance. Neuron 43:835–46

Wen Z, Zheng JQ. 2006. Directional guidance of nerve growth cones. Curr. Opin. Neurobiol.16:52–58

Willoughby D, Cooper DM. 2006. Ca2+ stimulation of adenylyl cyclase generates dynamicoscillations in cyclic AMP. J. Cell Sci. 119:828–36

Wittmann T, Waterman-Storer CM. 2001. Cell motility: Can Rho GTPases and microtubulespoint the way? J. Cell Sci. 114:3795–803

Woo S, Gomez TM. 2006. Rac1 and RhoA promote neurite outgrowth through formation andstabilization of growth cone point contacts. J. Neurosci. 26:1418–28

Xie XY, Barrett JN. 1991. Membrane resealing in cultured rat septal neurons after neurite tran-section: evidence for enhancement by Ca2+-triggered protease activity and cytoskeletaldisassembly. J. Neurosci. 11:3257–67

Xie Z, Samuels BA, Tsai LH. 2006. Cyclin-dependent kinase 5 permits efficient cytoskeletalremodeling: a hypothesis on neuronal migration. Cereb. Cortex 16(Suppl. 1):i64–68

Xu HT, Yuan XB, Guan CB, Duan S, Wu CP, Feng L. 2004. Calcium signaling in chemore-pellant Slit2-dependent regulation of neuronal migration. Proc. Natl. Acad. Sci. USA101:4296–301

Yacubova E, Komuro H. 2002a. Intrinsic program for migration of cerebellar granule cellsin vitro. J. Neurosci. 22:5966–81

Yacubova E, Komuro H. 2002b. Stage-specific control of neuronal migration by somatostatin.Nature 415:77–81

Yamamoto H, Fukunaga K, Goto S, Tanaka E, Miyamoto E. 1985. Ca2+, calmodulin-dependentregulation of microtubule formation via phosphorylation of microtubule-associated pro-tein 2, τ factor, and tubulin, and comparison with the cyclic AMP-dependent phosphory-lation. J. Neurochem. 44:759–68

Yao J, Sasaki Y, Wen Z, Bassell GJ, Zheng JQ. 2006. An essential role for beta-actin mRNA lo-calization and translation in Ca2+-dependent growth cone guidance. Nat. Neurosci. 9:1265–73

Yawo H, Kuno M. 1983. How a nerve fiber repairs its cut end: involvement of phospholipaseA2. Science 222:1351–53

Yuan XB, Jin M, Xu X, Song YQ, Wu CP, et al. 2003. Signalling and crosstalk of Rho GTPasesin mediating axon guidance. Nat. Cell Biol. 5:38–45

Yuste R, Bonhoeffer T. 2001. Morphological changes in dendritic spines associated with long-term synaptic plasticity. Annu. Rev. Neurosci. 24:1071–89

Zhang X, Poo MM. 2002. Localized synaptic potentiation by BDNF requires local proteinsynthesis in the developing axon. Neuron 36:675–88

Zheng JQ, Felder M, Connor JA, Poo MM. 1994. Turning of nerve growth cones induced byneurotransmitters. Nature 368:140–44

Zheng JQ. 2000. Turning of nerve growth cones induced by localized increases in intracellularcalcium ions. Nature 403:89–93

Zhou FQ, Cohan CS. 2001. Growth cone collapse through coincident loss of actin bundlesand leading edge actin without actin depolymerization. J. Cell Biol. 153:1071–84

Zhou FQ, Zhou J, Dedhar S, Wu YH, Snider WD. 2004. NGF-induced axon growth ismediated by localized inactivation of GSK-3β and functions of the microtubule plus endbinding protein APC. Neuron 42:897–912


Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.


Zhou Q, Homma KJ, Poo MM. 2004. Shrinkage of dendritic spines associated with long-termdepression of hippocampal synapses. Neuron 44:749–57

Zhou Q, Xiao M, Nicoll RA. 2001. Contribution of cytoskeleton to the internalization ofAMPA receptors. Proc. Natl. Acad. Sci. USA 98:1261–66

Ziv NE, Smith SJ. 1996. Evidence for a role of dendritic filopodia in synaptogenesis and spineformation. Neuron 17:91–102

Zuo Y, Yang G, Kwon E, Gan WB. 2005. Long-term sensory deprivation prevents dendriticspine loss in primary somatosensory cortex. Nature 436:261–65

404 Zheng · Poo

Ann

u. R

ev. C

ell D

ev. B

iol.

2007

.23:

375-

404.

Dow

nloa

ded

from

arj

ourn

als.

annu

alre

view

s.or

gby

Uni

vers

ity o

f C

alif

orni

a -

San

Fran

cisc

o on

10/

02/0

8. F

or p

erso

nal u

se o

nly.

Calcium Signaling in Neuronal Motility€¦ · a central role in the regulation of neuronal...

Documents

Transcript of Calcium Signaling in Neuronal Motility€¦ · a central role in the regulation of neuronal...