Dorsal-ventral patterning in the mammalian telencephalon

Dorsal-ventral patterning in the mammalian telencephalonKenneth Campbell

The telencephalon is the most diverse region of the brain with

respect to both morphology and neuronal subtypes. This fact

makes the task of unraveling the mechanisms underlying the

development of this brain region rather daunting. Recent

attempts to subdivide the embryonic telencephalon into distinct

progenitor domains along the dorsal–ventral axis have provided

an important framework on which to begin this process. These

progenitor domains are defined by the restricted expression of

transcriptional regulators and are proposed to give rise to

specific subtypes of neurons. Work over recent years has

provided important insights into the establishment and

maintenance of these progenitor domains in the developing

telencephalon.

AddressesDivision of Developmental Biology, Children’s Hospital Research

Foundation, 3333 Burnet Avenue, Cincinnati, OH 45229, USA

e-mail: [email protected]

Current Opinion in Neurobiology 2003, 13:50–56

This review comes from a themed issue on

Development

Edited by Magdalena Gotz and Samuel L Pfaff

0959-4388/03/$ – see front matter

� 2003 Elsevier Science Ltd. All rights reserved.

DOI 10.1016/S0959-4388(03)00009-6

AbbreviationsBMP bone morphogenetic proteinCGE caudal ganglionic eminence

DV dorsal–ventral

LGE lateral ganglionic eminence

MGE medial ganglionic eminence

RA retinoic acid

SHH sonic hedgehog

SVZ subventricular zone

VZ ventricular zone

IntroductionThe vertebrate telencephalon derives from the most

anterior portion of the developing CNS. This brain region

is instrumental in organizing intellectual functions and

voluntary movements. Two of the principal telencephalic

structures that regulate these processes are the cerebral

cortex and the basal ganglia (including both the striatum

and the globus pallidus). Although the cortex is located in

the dorsal telencephalon, its neuronal constituents derive

from both the dorsal and ventral halves of the embryonic

telencephalon: whereas cortical projection neurons arise

in the dorsal telencephalon from a thin neuroepithelium

[1], called the pallium (Figure 1), most of the interneur-

ons that populate cortical structures originate in the

ventral telencephalon (i.e. subpallium) and subsequently

migrate tangentially into the cortex [2,3,4��].

Neurons of the basal ganglia, by contrast, derive exclu-

sively from the ganglionic eminences of the ventral tele-

ncephalon (Figure 1). At rostral levels, the ganglionic

eminences form separate medial (MGE) and lateral

(LGE) elevations, whereas at caudal levels there is a

single eminence, known as the caudal ganglionic emi-

nence (CGE). The MGE is a very heterogeneous struc-

ture, giving rise to projection neurons of the pallidum and

basal forebrain [5,6], as well as to interneurons that

populate the ventral telencephalon and cortical structures

[3,4��,6,7]. The LGE produces the projection neurons of

the striatum [4��,5,6,8] and interneurons that migrate

rostrally to the olfactory bulb [4��,9]. Although the

LGE and CGE share many similarities, a recent study

has shown that the CGE gives rise to both projection

neurons and interneurons that are distinct from those

produced in either the LGE or the MGE [10�]. Thus,

the neuronal diversity present in many telencephalic

structures arises through the generation of neuronal sub-

types from localized subregions of the embryonic tele-

ncephalon and the subsequent distribution of these

neurons through radial or tangential migration.

An important issue in CNS development is what regulates

the regional production of specific neuronal subtypes.

Work on the developing spinal cord has shown that

distinct neuronal subtypes are generated from discrete

progenitor domains located along the dorsal–ventral (DV)

axis [11,12]. These progenitor domains are characterized

by the restricted expression of transcription factor genes

and seem to be established by the coordinated signaling

of bone morphogenetic proteins (BMPs) and sonic hedge-

hog (SHH) from the dorsal midline and ventral midline,

respectively [11,12]. Gene expression studies have estab-

lished that similar progenitor domains can be identified

along the DV axis of the developing telencephalon. This

review will cover recent work on the molecular mechan-

isms underlying the establishment and maintenance of

these telencephalic progenitor domains.

Regional subdivisions along the dorsal–ventral axis of the telencephalonThe morphological boundaries in the embryonic telence-

phalon do not always correlate with the progenitor

domains defined by gene expression. Notably, the bound-

ary between the dorsal and ventral halves of the tele-

ncephalon (i.e. the pallio-subpallial boundary) does not

lie at the angle of the pallium and LGE but is slightly

more ventral in the dorsal-most portion of the LGE

50

Current Opinion in Neurobiology 2003, 13:50–56 www.current-opinion.com

(Figure 1). This is evident from the restricted expression

of numerous transcription factors, including Pax6 on the

pallial side and Gsh2 on the subpallial side [13,14]. In the

subventricular zone (SVZ) and the mantle regions, the

pallio-subpallial boundary is marked by a stream of Pax6-

positive cells originating from the region where Pax6 and

Gsh2 meet in the ventricular zone (VZ) and continuing

down to the pial surface (Figure 1; [13–15]).

Recent studies [13,15–17] have suggested that the pal-

lium can been subdivided into separate ventral, lateral,

dorsal and medial compartments (Figure 1) that give rise

to projection neurons of the clastroamygdaloid complex,

lateral cortex, neocortex and hippocampus, respectively.

The ventral pallium was initially defined both by its

expression of Pax6 in the VZ and Tbr1 in the mantle

region and by its lack of Emx1 expression [15,16]. Recent

work has shown that the VZ of the ventral pallium

uniquely expresses the homeobox gene Dbx [13] and

the putative Wnt antagonist SFRP2 [18].

Unlike the ventral pallium, the specific boundaries of the

other pallial domains are not as easily marked by discrete

gene expression. In these regions, graded gene expression

is more common. For example, Emx1, Emx2 [19,20] and

Lhx2 [21��] all show high expression in the medial pal-

lium, with a progressive reduction of expression in more

ventral regions. Conversely, Pax6 and Tbr2 show the

opposite profile with their highest expression in the VZ

of the ventral and lateral pallium [13,14,17].

In the subpallium, many genes are expressed in both the

LGE and MGE, including Gsh2 in the VZ [22] and

members of the Dlx gene family (i.e. Dlx1, Dlx2, Dlx5and Dlx6) in the VZ and the SVZ [23]. The ventromedial

telencephalon, including the MGE, steptum and the

preoptic area, expresses Nkx2.1 [24,25]. Given the con-

siderable heterogeneity of the ventromedial telencepha-

lon with respect to the oligodendrocytes [26�,27�] and the

different interneurons that it generates [3,7], it seems

likely that future studies will identify separate progenitor

subdomains in this telencephalic region as well.

Recently, the LGE has been divided into a small dorsal

domain (dorsal LGE) and a larger ventral domain (ventral

LGE) (Figure 1; [13]). The dorsal LGE expresses the Ets

gene Er81 [13]. Although this gene is expressed in the

VZ, protein expression is observed only in the SVZ of the

dorsal LGE. This Er81-positive SVZ domain has been

suggested to give rise to interneurons that migrate in the

rostral migratory stream to populate the olfactory bulb

[28�]. Progenitors in the SVZ of the ventral LGE uniquely

express the LIM homeobox protein Islet-1 and generate

striatal projection neurons [14,28�].

Figure 1

MGE

dLGE

vLGE

VP

LP

DPMP

MGE

LGE

pallium

VZSVZ

Pallio-subpallialboundary

Dorsal

Ventral

Current Opinion in Neurobiology

Coronal hemisections of the mouse telencephalon at embryonic day 12.5, showing morphologically defined structures and the progenitor

subdomains identified by restricted expression of transcription factor genes. The ventricular zone (VZ) extends along the whole DV axis and contains

precursor cells. The subventricular zone (SVZ, indicated by broken blue lines) also contains precursor cells, which is a unique feature of the

telencephalon. Note the placement of the DV boundary (i.e. pallio-subpallial boundary) in the dorsal portion of the LGE. Broken red lines indicate the

approximate boundaries between distinct telencephalic progenitor domains (see text for details). dLGE, dorsal LGE; DP, dorsal pallium; LP, lateralpallium; MP, medial pallium; vLGE, ventral LGE; VP, ventral pallium.

Dorsal-ventral patterning in the mammalian telencephalon Campbell 51

www.current-opinion.com Current Opinion in Neurobiology 2003, 13:50–56

Dorsal telencephalic patterningThe roof plate is thought to have an essential role in

patterning the dorsal spinal cord, primarily through the

expression of BMPs [11,12]. A recent study has assessed

the role of the roof plate in dorsal telencephalic patterning

[21��]. In this study, genetic ablation of the telencephalic

roof plate resulted in a severely reduced expression of

Lhx2 and a severe reduction in cortical size. A require-

ment for BMPs was implied from these results because

the dorsal midline of the telencephalon expresses numer-

ous BMPs [29]. Indeed, explant studies support a role for

BMPs in dorsal telencephalic development [29] and, in

particular, in the expression of Lhx2 [21��].

The requirement for BMP signaling in dorsal telence-

phalic patterning has recently been assessed by condi-

tionally inactivating the BMP receptor 1a specifically in

the mouse telencephalon [30�]. Although the choroid

plexus (a dorsal midline derivative) does not form prop-

erly in these conditional mutants, the telencephalon

seems to be patterned correctly along the DV axis.

Compensation by the BMP receptor 1b in the dorsal-

most telencephalon (i.e. medial and dorsal pallium) was

not observed, indicating that BMP signaling is required

absolutely for midline development but other factors can

organize dorsal patterning in the telencephalon.

The dorsal midline of the telencephalon is also known to

express Wnt molecules [31], and Wnt signaling is

required for hippocampal development (i.e. medial pal-

lium) [32,33]. Furthermore, certain Wnts are also

expressed throughout the pallial VZ at early stages of

telencephalic development [31,34] and thus may have a

broader role in patterning the dorsal telencephalon. Inter-

estingly, ablation of the roof plate in the telencephalon

also resulted in the loss of the Wnt2b expression from the

dorsal midline [21��], suggesting that the observed phe-

notype may result from the combined loss of BMP and

Wnt signaling.

A recent study has identified a telencephalic enhancer of

the Emx2 gene that is expressed at its highest levels in the

medial and dorsal pallium (similar to Lhx2) [35�]. This

enhancer contains requisite binding sites for both Smad

and Tcf proteins, which are transcriptional mediators of

BMP and Wnt signaling, respectively. In addition, both

BMPs and Wnts can activate this DNA enhancer in

midbrain explants. Thus, it may be that BMP signaling

from the dorsal midline is functionally redundant with

Wnt signaling in specifying certain aspects of dorsal

telencephalic fates.

The downstream effects of BMP and/or Wnt signaling in

the dorsal telencephalon ultimately involves the combi-

natorial actions of transcription factors such as Emx1,

Emx2 and Lhx2, which function to specify and to expand

the medial and dorsal pallium. This is most evident in the

Lhx2 mutants, which lack most of the hippocampus and

neocortex [21��,36,37]. The Emx mutants do not show as

marked phenotypes in the dorsal telencephalon as do the

Lhx2 mutants, although hippocampal development is

impaired in Emx2 mutants [38,39]. This is not thought

to result from altered specification, however, but rather

from reduced growth and maturation [40].

Another transcription factor that is crucially involved in

dorsal patterning is the zinc-finger gene Gli3[41,42,43��]. Loss of Gli3 function results in a loss of

Emx gene expression as well as the ectopic expression of

certain genes characteristic of ventral telencephalic pro-

genitors, such as Gsh2. With respect to the latter pheno-

type, a recent study has shown that Gli3 is required to

antagonize the ventralizing signal SHH in the dorsal

telencephalon [43��]. It is currently unclear whether

Gli3 lies upstream, downstream or in a parallel pathway

with BMP and Wnt signaling.

Ventral telencephalic patterningThe secreted glycoprotein SHH is required for ventral

development at caudal levels of the developing CNS

(reviewed in [11,12]), and many studies have shown that

SHH is also involved in patterning the ventral telence-

phalon [44–48]. Results obtained from the analysis of

Shh-null mice [49] also support a role for SHH in tele-

ncephalic patterning, but it does not seem to be required

for all aspects of ventral telencephalic development.

Although these mutants lack any sign of MGE develop-

ment, such as expression of Nkx2.1 [43��,50], many of

them express genes normally found in both the MGE and

LGE, such as Gsh2 and Dlx2, as well as the LGE-specific

cellular retinol-binding protein 1 ([43��]; and H Toresson,

K Campbell, unpublished data). Thus, SHH is required

for ventromedial (i.e. MGE) telencephalic development,

but aspects of ventrolateral (i.e. LGE) telencephalic

patterning can occur in its absence. Although it is cur-

rently unclear whether dorsal LGE characteristics are

present in the Shh-null mice, Islet-1 cells (i.e. ventral

LGE) can be found (H Toresson, K Campbell, unpub-

lished data).

As mentioned above, a role of Gli3 is to antagonize SHH

signaling. Recent work has shown that this is a mutually

antagonistic interaction with SHH repressing Gli3 func-

tion both in the ventral spinal cord [51] and in the tele-

ncephalon [43��]. In the spinal cord of Shh�/�;Gli3�/�

mutants, ventral patterning is greatly improved over that

observed in single Shh mutants, however, the ventral-

most cell types (i.e. the floor plate and V3 neurons) do not

form [51]. This may be different in the telencephalon,

because Shh�/�;Gli3�/� and even Shh�/�;Gli3þ/� mutants

show Nkx2.1 expression and a morphologically distinct

MGE [43��]. It remains unclear, however, whether

the ventral-most telencephalic regions (e.g. preoptic area)

are rescued in the Shh�/�;Gli3�/� mutants. Notably,

52 Development


patterning in the dorsal telencephalon of Shh;Gli3 double

mutants is improved over that in Gli3 single mutants,

indicating that excessive SHH signaling is involved in the

manifestation of the Gli3 mutant phenotype.

It is currently unknown what patterns the telencephalon

in the absence of SHH and Gli3. Other hedgehog proteins

are not likely candidates because double mutants of

Smoothened (an essential component of SHH signaling

[52]) and Gli3 also show improved DV patterning similar

to that observed in the Shh�/�;Gli3�/� embryos [43��]. As

suggested by Rallu et al. [43��] other (potentially novel)

signaling pathways may direct DV patterning in the

absence of SHH and Gli3. If this is true, it will be

interesting to determine whether these pathways nor-

mally have a role in DV patterning or if they do so only as

a compensatory mechanism.

The source of SHH for telencephalic DV patterning

remains unclear. Unlike the developing spinal cord, the

telencephalon lacks both a floor plate and the underlying

mesoderm expressing SHH [44]. In addition, the expres-

sion of Shh in the ventral telencephalon is an unlikely

source for patterning because it coincides with, rather than

precedes, ventral specification (e.g. see [24]). Previously,

the ventral midline of the diencephalon was suggested to

be the source of SHH for telencephalic ventralization [44];

however, a more recent study has proposed that SHH

from the node controls this process [46]. If this is true,

then the initiation of ventral patterning in the telence-

phalon occurs much earlier than was previously thought.

Patterning the intermediate telencephalonThe intermediate region of the telencephalon includes

the LGE, as well as the ventral and lateral pallium, and is

divided by the pallio-subpallial boundary. Although sig-

nals from both the dorsal and the ventral aspects of the

telencephalon probably have an impact on the patterning

of this region, it is also likely that distinct lateral signals are

involved (Figure 2). Indeed, these putative lateral signals

may contribute to the expression of ventrolateral genes in

the ventral midline of the Shh mutant (see above).

The expression profiles of certain genes in the intermedi-

ate telencephalon also support the notion of distinct

lateral signals. For example, Pax6 and Gsh2 show graded

expression patterns in the dorsal and ventral portions,

respectively, with their highest expression occurring at

the pallio-subpallial boundary [13,14]. Previous work has

shown that a SHH-independent retinoic acid (RA) path-

way can pattern the intermediate region of the developing

spinal cord [53]. Interestingly, at early stages of telence-

phalic patterning, mesenchymal cells in the olfactory

placodes that produce RA are in close proximity to the

ventral telencephalon and induce the expression of reti-

noid reporter genes in the ventrolateral region [54]. Thus,

RA may participate in patterning the telencephalon.

As mentioned above, the pallio-subpallial boundary

divides the telencephalon into a dorsal and ventral por-

tion. Pax6 and Gsh2 are crucial for the positioning of

this boundary through the regulation of mutually re-

pressive genetic programs [13,14]. The telencephalic

subdomains lying directly on each side of the pallio-

subpallial boundary (i.e. the dorsal LGE and the ventral

pallium) are most dependent on correct positioning of

this boundary. In the absence of Pax6, genes character-

istic of the dorsal LGE become ectopically expressed

early in the ventral pallium and subsequently spread as

far as the dorsal pallium [13,28�]. The opposite is true

in Gsh2 mutants, in which ventral pallial markers are

ectopically expressed in the LGE [13]. These altera-

tions in gene expression do not represent a transforma-

tion of the dorsal LGE into the ventral pallium in Gsh2mutants or vice versa in Pax6 mutants, because other

markers of DV identity are expressed normally in these

mutants [14].

Figure 2

Wnts

BMPs

RA??

SHH?

MGE

vLGE

dLGE

VP

LP

DPMPrp

Current Opinion in Neurobiology

The mouse telencephalon at embryonic day 10, showing the extrinsic

signals that establish different progenitor domains along the DV axis.BMPs are most highly expressed in dorsal–medial portions of the

telencephalon, where they are required to act locally for midline

development. Wnts are expressed throughout the pallium and may

function more broadly in dorsal specification than BMPs. Although SHH

is required for ventromedial specification, some aspects of ventrolateral

patterning can occur in its absence. DV patterning can occur in the

absence of both Shh and Gli3, suggesting the existence of alternative

signals and/or pathways in ventralizing the telencephalon. Lateral

signals are proposed to participate in patterning the intermediate

telencephalon. RA may be involved in this process. dLGE, dorsal LGE;

DP, dorsal pallium; LP, lateral pallium; MP, medial pallium; rp, roof

plate; vLGE, ventral LGE; VP, ventral pallium.



The fact that Pax6 and Gsh2 do not control all aspects of

the DV identity in the intermediate telencephalon indi-

cates that parallel and overlapping genetic pathways are

also involved. Indeed, Gli3 mutants show ectopic ventral

gene expression in the pallium similar to that seen in Pax6mutants, despite the fact that Pax6 seems to be normally

expressed [41,43��]. In addition, a recent study [55��] has

shown that in Emx2�/�;Pax6�/� mutants dorsal patterning

is considerably more perturbed than in single Pax6mutants. Although Emx2 mutants do not show overt

patterning defects in the intermediate telencephalon,

removal of Pax6 gene function from the Emx2 mutant

background causes the whole pallium to lose its dorsal

identity [55��]. In the absence of pallial gene expression,

markers of the ventral LGE (e.g. Islet-1) are expressed in

the dorsal telencephalon of these double mutants, sug-

gesting that there is a transformation of the pallium into

subpallium. Thus, correct DV patterning in the telence-

phalon relies on the superimposition of several genetic

pathways.

ConclusionsWork carried out to date has provided a substantial

framework on which to uncover the mechanisms that

control DV identity in the developing telencephalon.

The identification and refinement of progenitor domains

along the DV axis has been and will continue to be central

to this endeavor. Signals from each of the dorsal, ventral

and possibly lateral aspects of the developing telence-

phalon participate in the establishment and maintenance

of these progenitor domains, by regulating both separate

and overlapping genetic pathways (Figure 2). In future

studies it will be important to define further the roles of

BMPs, RA, SHH and Wnts, as well as other as yet

unknown signals, in DV patterning of the telencephalon.

Many of the mechanisms involved in patterning the DV

axis of the spinal cord are also at work in the telence-

phalon. What is it, then, that makes the mature telence-

phalon so much more complex than the spinal cord? A

recent study has provided evidence that, in addition to

spatial (e.g. DV) patterning, temporal patterning events

contribute extensively to generating neuronal diversity in

the Drosophila CNS [56]. Because the telencephalon

shows a very protracted period of neurogenesis as com-

pared with the spinal cord, it may be that different

neuronal subtypes are generated from each telencephalic

progenitor domain at specific time points during devel-

opment. Thus, it will be important in future work to

establish a connection between DV patterning and tem-

poral patterning to account for the generation of all of the

subtypes of neurons present in the telencephalon.

UpdateA recent study has demonstrated a role for the orphan

nuclear receptor TLX in the establishment of the pallio-

subpallial boundary and maintenance of ventral pallial

identity [57�]. Interestingly, a genetic interaction between

TLX and Pax6 was found to be crucial for this process.

AcknowledgementsI thank Doug Epstein, Magdalena Gotz, Mike Matise and Jan Stenman forcritically reading the manuscript, and Gord Fishell for providing preprints ofpapers discussed in the review.

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This study addresses the role of BMPs in patterning the dorsal telence-phalon by conditional inactivation of the BMP receptor 1a. The resultsindicate that loss of BMP signaling in the dorsal telencephalon results in anormal dorsal–ventral pattern but a lack of normal development of the

choroid plexus, suggesting a local role for BMPs only in the dorsaltelencephalic midline.

31. Grove EA, Tole S, Limon J, Yip L, Ragsdale CW: The hem of theembryonic cerebral cortex is defined by the expression ofmultiple Wnt genes and is compromised in Gli3-deficient mice.Development 1998, 125:2315-2325.

32. Lee SM, Tole S, Grove E, McMahon AP: A local Wnt-3a signal isrequired for development of the mammalian hippocampus.Development 2000, 127:457-467.

33. Galceran J, Miyashita-Lin EM, Devaney E, Rubenstein JL,Grosschedl R: Hippocampus development and generation ofdentate gyrus granule cells is regulated by LEF1. Development2000, 127:469-482.

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35.�

Theil T, Aydin S, Koch S, Grotewold L, Ruther U: Wnt and Bmpsignalling cooperatively regulate graded Emx2 expressionin the dorsal telencephalon. Development 2002,129:3045-3054.

In this paper, a telencephalic enhancer for the Emx2 gene is identified andshown to contain requisite Smad- and Tcf-binding sites, implicating bothBMPs and Wnts in the regulation of this dorsal telencephalic gene.

36. Porter FD, Drago J, Xu Y, Cheema SS, Wassif C, Huang SP, Lee E,Grinberg A, Massalas JS, Bodine D et al.: Lhx2, a LIM homeoboxgene, is required for eye, forebrain, and definitive erythrocytedevelopment. Development 1997, 124:2935-2944.

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40. Tole S, Goudreau G, Assimacopoulos S: Grove EA: Emx2 isrequired for growth of the hippocampus but not forhippocampal field specification. J Neurosci 2000, 20:2618-2625.

41. Theil T, Alvarez-Bolado G, Walter A, Ruther U: Gli3 is required forEmx gene expression during dorsal telencephalondevelopment. Development 1999, 126:3561-3571.

42. Tole S, Ragsdale CW, Grove EA: Dorsoventral patterning of thetelencephalon is disrupted in the mouse mutant extra-toes(J).Dev Biol 2000, 217:254-265.

43.��

Rallu M, Machold RP, Gaiano N, Corbin JG, McMahon AP, FishellG: Dorsoventral patterning is established in the telencephalonof mutants lacking both Gli3 and Hedgehog signaling.Development 2002, 129:4963-4974.

The results of this paper provide evidence for the cross-repressiveactivities of SHH and Gli3 in the telencephalon. In the absence ofboth Shh and Gli3 gene function, dorsal–ventral patterning is markedlybetter than in either single mutant. These findings suggests that anothersignal or signals can pattern the telencephalon in the absence of SHHand Gli3.

44. Ericson J, Muhr J, Placzek M, Lints T, Jessell TM, Edlund T: Sonichedgehog induces the differentiation of ventral forebrainneurons: a common signal for ventral patterning within theneural tube. Cell 1995, 81:747-756.

45. Kohtz JD, Baker DP, Corte G, Fishell G: Regionalization within themammalian telencephalon is mediated by changes inresponsiveness to Sonic Hedgehog. Development 1998,125:5079-5089.

46. Gunhaga L, Jessell TM, Edlund T: Sonic hedgehog signaling atgastrula stages specifies ventral telencephalic cells in thechick embryo. Development 2000, 127:3283-3293.

47. Gaiano N, Kohtz JD, Turnbull DH, Fishell G: A method for rapidgain-of-function studies in the mouse embryonic nervoussystem. Nat Neurosci 1999, 2:812-819.



48. Corbin JG, Gaiano N, Machold RP, Langston A, Fishell G: The Gsh2homeodomain gene controls multiple aspects of telencephalicdevelopment. Development 2000, 127:5007-5020.

49. Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H,Beachy PA: Cyclopia and defective axial patterning in micelacking Sonichedgehoggene function. Nature 1996,383:407-413.

50. Pabst O, Herbrand H, Takuma N, Arnold HH: NKX2 geneexpression in neuroectoderm but not in mesendodermallyderived structures depends on sonic hedgehog in mouseembryos. Dev Genes E 2000, 210:47-50.

51. Litingtung Y, Chiang C: Specification of ventral neuron types ismediated by an antagonistic interaction between Shh and Gli3.Nat Neurosci 2000, 3:979-985.

52. Ingham PW, McMahon AP: Hedgehog signaling in animaldevelopment: paradigms and principles. Genes Dev 2001,15:3059-3087.

53. Pierani A, Brenner-Morton S, Chiang C, Jessell TM: A sonichedgehog-independent, retinoid-activated pathway ofneurogenesis in the ventral spinal cord. Cell 1999,97:903-915.

54. LaMantia AS, Colbert MC, Linney E: Retinoic acid induction andregional differentiation prefigure olfactory pathway formationin the mammalian forebrain. Neuron 1993, 10:1035-1048.

55.��

Muzio L, DiBenedetto B, Stoykova A, Boncinelli E, Gruss P,Mallamaci A: Conversion of cerebral cortex into basal ganglia inEmx2�/� Pax6Sey/Sey double-mutant mice. Nat Neurosci 2002,15:15.

In this study, loss of function for both Pax6 and Emx2 is shown to result ina respecification of the pallium towards subpallial fates typical of theventral LGE (i.e. striatal specification). Because Emx2 mutants do notshow overt patterning defects, these findings reveal a role for Emx2 in theabsence of Pax6 gene function.

56. Isshiki T, Pearson B, Holbrook S, Doe CQ: Drosophila neuroblastssequentially express transcription factors which specify thetemporal identity of their neuronal progeny. Cell 2001,106:511-521.

57.�

Stenman J, Yu RT, Evans RM, Campbell K: TLX and Pax6cooperate genetically to establish the pallio-subpallialboundary in the embryonic mouse telencephalon. Development2003, in press.

See update.

56 Development


Dorsal-ventral patterning in the mammalian telencephalon

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