Neurogenesis and Neuronal Migration -...
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Neurogenesis and NeuronalMigration
Paul Garrity
March 1, 2004
7.68J/9.013J
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Development of corticallayers
• Cortex starts outas monolayerepithelium
• Nuclei/cells moveup and downaccording to theircell cycle phase
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Development of corticallayers
• Neurogenesisinitiates:– Some cells begin to
leave cell cycle -- rise• Form preplate
– Cajal-Retzius cells– Subplate cells
– Many cells continue todivide
• Ventricular zone (VZ)
– Axons enter cortex:Intermediate Zone (IZ)(bidirectional cortex/thalamusconnections)
Subplate cells -
Cajal-Retzius cells -
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Development of corticallayers
• Newly generatedneurons migratethrough subplate
• Stop beneathCajal-Retzius cells
• Form cortical plate
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Development of corticallayers
• Cortical Platedifferentiatesto formcortical layers
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Development of corticallayers
• As corticalplate forms
• Subpopulationof proliferatingcells formsabove VZ :
• SubventricularZone (SVG)
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Subventricular Zone
• Secondary zone ofneurogenesis
• Proliferate through post-natal period– Generate multiple cell
types:• Glia
• Neurons
• Include cells that migrate toolfactory bulb
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Are cortical layersgenerated in any temporal
sequence?• Birthdating
analysis• Inject mother with
tritiated thymidine• Label dividing cells• Diluted with
subsequentdivisions
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Birthdating of cortical layersin rodents
• Inject at multipletime points
• Detect usingautoradigraphy
• Answer: Corticallayers generated“inside-out”
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Birthdating in monkeycerebral cortex
Primates: Cortical layers
also generated“inside-out”
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Radial migration
• Post-mitoticneurons migrateaway fromventricular zonetoward brainsurface
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Pattern of migration
• Newlygenerated cellsmigratebeyond earliercells
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Neuron growing along glialcell in culture
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Migration along radial glialcells
• Radial glial cellsspan thedevelopingcortex
• Neurons appearto migrate inclose contactalong them
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Neuronal migration
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How is neuronal migrationregulated?
• Molecularpathwayscontrollingneuronalmigrationidentifiedthroughhuman andmousemutants:
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The reeler mutant mouse
• Birthdatinganalysis ofreeler mutant:
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The reeler mutant mouse
• Birthdatinganalysis ofreeler mutant:
• Timing oflayerproduction isinverted
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Anatomy of developingcortex in reeler
wild type reeler
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Molecular identification ofReelin
• Secreted protein
• Produced by Cajal-Retziuscells
wild type reeler
Reelin
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Model for Reelin function
• Signal promotingmigration alongand/or detachmentfrom radial glial cell
Reelin
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The Reelin pathway
• Other mutant mice found with samephenotype: eg., Dab1
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Dab1
• Cytoplasmic adaptor protein
• Binds to receptors
• Binds to cytoplasmic protein kinases
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Receptors for Reelin
• Animals double mutantfor ApoER2/VLDLRresemble reeler
• Well-known lipoproteinreceptors
• Expressed in migratingneurons
• Bind ReelinReelin also binds integrins --
co-receptor?
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Reelin signaling pathway
ApoER2/VLDLRbind Dab1!
-- in addition:mutants in P35and cdk5 (whichfunctiontogether askinase complex)have similarphenotypes toreeler
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Disorders of neuronalmigration in human disease
enlarged ventriclesreduced white matter
decreased folding
cerebellum
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Regulators of migrationfound as human disease
genes
Lissencephaly(smooth brain)
Cobblestone cortex
Corticalheterotopia[sideview]
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Cortical layering in patients
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Schematic of how layeringdefects may be generated
Normal Classical Lissencephaly Cobblestone cortex Cortical Heterotopia
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Cobblestone cortex
• Abnormal basallamina/extracellular matrix– Fukutin: glycoprotein/glycolipid
modifying enzyme
– Muscle-eye-brain (MEB) diseaseprotein: protein glycosylatingenzyme
– May disrupt basal laminasurrounding brain
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Lissencephaly genes:microtubule regulators involved
in nuclear migration• Genes that interact with microtubules:
– Lis1 (homolog of NudF -- required for nuclearmigration in Asperigillus nidulans )
• Interacts with microtubule organizer (centrosome)• Interacts with Dynein (microtubule motor protein) --
multiple roles including nuclear movement
– DCX (microtubule binding protein)
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X-linked periventricularheterotopia
• Mutant in Filamin– Actin-associated protein
– Associates with multiple regulators ofactin cytoskeleton
• Both actin and microtubulecytoskeletons important in migration
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Tangential migration incortex
• Embryological and labellingexperiments demonstratedthat not all cortical cells arisefrom radial migration
• Lose GABA-ergicinterneurons in mutant micewith disrupted LGE and MGEdevelopment
• GABA-ergic interneuronsmigrate in from region ofbasal telencephalon (medialganlionic eminence, MGE)
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Molecular mechanisms oftangential migration
• Differs from radial migration:– Does not require reelin, dab or cdk5
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Regulators of tangentialmigration
• Semaphorins: family of guidancecues: attract and repel cells andprocesses– Sema 3: secreted signal
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Regulators of tangentialmigration
• Semaphorin 3 receptors:– Neuropilin (ligand-binding subunit)
– Plexin (trans-MB signal transducer)
– L1 (modulator)
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Semaphorin signaling intangential migration
• Neuropilin (receptor) expressed onmigrating cells
• Semaphorin 3 expressed on pathway• Examined effect of disrupting
Neuropilin signaling via:– Nrp2 knock-out mouse– Nrp1 dominant-negative
• How to make a dominant-negative receptor?
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Dominant-negativeneuropilin
• Truncation of cytoplasmic domain– No effect
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Neuropilin dominant-negative receptor
• Neuropilin functions:– Bind Sema 3
– Initiate signal transduction
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Dominant-negativeneuropilin
• Truncation of cytoplasmic domain– No effect
• Truncation in extracellular domain-Dominant-negative
-Still binds Sema3
-Signaling fails
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Dominant-negativeneuropilin
• Truncation of cytoplasmic domain– No effect
• Truncation in extracellular domain-Dominant-negative
-Still binds Sema3
-Signaling fails x
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Neuropilin signaling regulatestangential migration
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Dorsal/Ventral Axispatterning
• Structures along DVaxis of Neural Tube– Roof plate (R)
– Floor plate (F)
– Notochord (N)
– Neural crest (NC)
– Paraxialmesoderm/somites (S)
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Neural Crest Cells
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Generation of appropriatenumbers of cells
• A) Non-self-renewingprogenitor:generates twodifferentiating cells
• B) Self-renewing:generates at leastone cell same asparent
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Nervous system progenitors
• Nervous systemsundergo enormousexpansion in cellnumber duringdevelopment
• Relies on cells that canself-renew: stem cells
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Stem cell divisions• Symmetric
division:– Generates two
stem cells
•Asymmetricdivision:
–Regenerates stemcell and produces anovel cell
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Stem cells in thehematopoietic system
• Plutipotent stem cellscan generate stemcells withprogressivelyrestricted potentialfates
• Restriction canproceed in more thanone step as generateincreasinglycommitted progenitors
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Neural stem cells
• Key properties:
• Multipotent -- generate multipledifferent types of progeny
• Self-renewing
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Sample genealogy ofcortical neuronal stem cell
• Self-renewing
• Undergo symmetric(diamond, circle) andasymmetric (*)divisions
• Multipotent: generatesneurons (N) and glia (_)
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Stem cell divisions• Symmetric
division:– Generates two
stem cells
•Asymmetricdivision:
–Regenerates stemcell and produces anovel cell
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Shifts in fraction of patternof stem cell division with
time
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Radial glial cells:
• Classic view:• Radial glial cells act as substrates for
neural migration• A distinct population of cells generates
neurons
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Radial glial cells: (c. 2001)
• Radial glial cells are mitotically active• What do they produce?
– Infect radial glia with GFP retrovirus– Identify single, labelled radial glia cells at 24h– Wait 2 more days ( forms a clone of cells )
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Radial glial cells: more thanjust substrate for migration
• What do labelled radialglial cells produce?– See labelled:
• mitotically active radial glia --divide in VZ
• post-mitotic neurons
– Post-mitotic neuronsmigrate along clonallyrelated radial glial cells --
Fishell and Kriegstein (2003) Current Opinion in Neurobiology 13:34
![Page 56: Neurogenesis and Neuronal Migration - web.mit.eduweb.mit.edu/9.013/www/lectures/07_PG_Neurogenesis_Migration.pdf · Development of cortical layers •Cortex starts out as monolayer](https://reader030.fdocuments.us/reader030/viewer/2022040701/5d5e063c88c99328118b6e65/html5/thumbnails/56.jpg)
Current models for RadialGlial Cell asymmetric
division
Fishell and Kriegstein (2003) Current Opinion in Neurobiology 13:34
![Page 57: Neurogenesis and Neuronal Migration - web.mit.eduweb.mit.edu/9.013/www/lectures/07_PG_Neurogenesis_Migration.pdf · Development of cortical layers •Cortex starts out as monolayer](https://reader030.fdocuments.us/reader030/viewer/2022040701/5d5e063c88c99328118b6e65/html5/thumbnails/57.jpg)
Current models for RadialGlial Cell asymmetric
division• Current evidence
suggests thatboth“translocation”and “migration”are used
Fishell and Kriegstein (2003) Current Opinion in Neurobiology 13:34