- Positional information dictates gene expression profile (and ultimate fate) of neural precursors in Drosophila 

- Gene expression in neuroblasts varies with rostro-caudal position. 

- Gene expression will vary with anterior-posterior and dorso-ventral position. A grid is therefore set up such that each neuroblast is specified by its position in the embryo. 

- Both intrinsic (based on body position) and extrinsic cues specify neuroblast identity. (ex. Drosophila dpp gradient. Note: dpp = vertebrate BMP4) 

- the identity of cells is said to be purely "lineage dependent" when fates are determiend by (intrinsic) parentage rather than by (extrinsic) region (ie. if you transplant a neuroblast cell from one region to another, the fate of its progeny will not change). Cell fate in Drosophila and ther invertebrates (C. elegans) appears to be more lineage dependent, than in vertebrates. 

The Ventricular zone (VZ) is adjacent to the lateral ventricle at an important region for generating early neural cells (arrowheads indicate the pial or outer surface of human cortex at embryonic day 30 (~ time of neural tube closure).

The number of neurons are lowered in number.  

1. Initially the cerebral wall consists entirely of neuroepithelial cells (with some mitotic cells)

2. Some predecessor neurons, migrating into the cortical primordium from the supallium initiates the formation of the preplate at embryonic day E31-32

3. Post-mitotic neurons, in the VZ, migrate outwards o join the predecessor neurons

4. Mitotic cells start to accumulate at th basal border of the VZ starting the formation of the subventricular zone before the cortical plate begins to form 

5. radially migrating neurons initiate formation of the CP. The emerging CP horizontally divides PP into the outer marginal zone and a compartment that contains heterogeneous cell populations. At this stage the cell density in the compartment between the SVZ an dCP is nearly homogeneous, and the boundary between the intermediate zone and the incipiet subplate is unclear so this compartment is calle d the intermediate/subplate zone

6. At the end of the human embronic period, the lower part of the IZ is seen as a cell-sparse area. Extrinsic axons invade this area in the most differentiated part of the ventrolateral cortex. 

What occurs in mammalian Neurogenesis? 

1. When the cortex is very thinm there are neuroepithelial cells which divides symmetrically to generate more neuroepithelial cells. Some become radial glia and some become neurons directly or indirectly through intermediate progenitor cells. 

2. Oligodendrocytes are derived from the RG through intermediate progenitor cells that make oligodendrocyte progenitors 

3. As progeny from RG and IPCs move into the mantel for differentiation, the brain thickens and further elongates the RG cells

4. Radial glia have apical-basal polarity and RG contacts the ventricles where they project a single primary cilium up towards the meninges, basal lamina and blood vessils

5. At the end of the embryonic development, most RG begin to detach from the apical side and convert into astrocytes while oIPC production continues

6. A subpopulation of RG remains apical contact and function as neural stem cells in adults

1. Neural stem cells in the early neuroepithelium extend from the ventricle to the pia

2. Many radial glia contact the ventricular and pial surfaces. Radial glia are also neural stem cells. They are known to divide symmetrically or asymmetrically to produce neurons that migrate into the cortex along a process of their progenitor. Radial glia produce neurons directly or indirecly through intermediate progenitor cell types, IPCs

3. Radial glia transform into cortical astrocytes later in development. During adult life, cells derived from radial glia reside in the adult subventricular zone. These astrocyte-like cells behave as neural stem cells in that they self-renew and prduce nerons, possibly through intermediate neuronal progenitors.  

1. Toclassical embryologists, theventricularsurface was considered thetop of the

proliferative zone andthelayers were  describeddownwards fromthe ventricular

towards the pialsurface (dorsaloutercortex). Thus youare goingdownwhen

moving away from thesubventricularzone(SVZ).

•  Similarly,theterm‘apical’tradi5onallysignifiesorienta5ontowards,orproximity

to,theventricularsurface,whereas‘basal’referstofeaturesfurtherfromthe

ventricle.Thenomenclatureremainsinusetothisday(sigh!)

•  However,tothecontemporaryobserver,focusedontheeventualfunc5onsofthe

cerebralcortex,itislogicaltoviewthepialsurfaceasthetopandthereforetothink

ofstructuresorlayersthatareclosertothepiaasbeingsuperficial,outerorapical.

Thisistheconven5onfornumberingthematurelayersofthecerebralcortex.

Layers(1-3)closertothedorsalsurface(pia)thanlayer4—thegranularlayer—

arecalledsupragranular;whereas,deeperlayers(5-6)areinfragranular.

•  Equally,themajordendritesofpyramidalneurons,whicharedirectedtowardsthe

pia,arecalled‘apical’dendrites,whereasthoseatthelowerpoleofthecellare

‘basal’dendrites—thisnomenclatureisdirectlyoppositeinorienta5ontothatof

theapicalandbasalpolesofearlyneuroepithelialcells

1. cortical layers of neurons in te adult mammalian brain (layer 1 is the most outer layer of cells) 

2. the first born neurons are subplate or predecessor cells (inner) and Cajal-Retzius cells (outer)

3. Later, other neurons making the in-between layers migrate past te intermediate zone, up to the cortical plate. 

1. Layer V and VI (projection neurons to subcortical regions) 

2. Layer IV (interneruons receiving input from the thalamus) 

3. Layer II and III (projection neurons usually within cortex of the same or opposite hemisphere)

1. Supragranular layers: 

- layers I to III

- The supragranular layers are the primary origin and termination of intracortical connections, which are either associational (ie. with other regions of the same hemisphere), or commissural (ie. connection to the opposite hemisphere, primarily through the corpus callosum. The supragranular portion of the cortex is highly developed in humans. 

2.internal granular layer: 

- layer IV

- receives the thalamocortical connections, espcially fromthe specific thalamic nuclei. THis is most prominent in the primary sensory cortices. 

3. Infragranular layers: 

- layers V and VI

- primarily connect the cerebral cortex with subcortical regions. These layers are most developed in motor cortical areas. The motor areas have extremely small or non-existent granula layers and are often called "agranular cortex." Layer V gives rise to all of the principal cortical efferent projections to basal ganglia, brain stem and spinal cord. Layer VI, the multiform or fusiform layer, projects primarily to the thalamus. 

  Post mitoticimmatureneuronsmigratefromtheventricularzone(VZ).As

migrationfromtheVZcontinues,corticallaminationisestablished inaninside-outfashion.Theearliest-bornneuronsendupdeepinthecortex,aslater-born

neuronsmigratepastthemtowardthepialsurfacetoestablishmoresuperficial

layersofthecortex.Thelatest-bornneuronsresidenearthepialsurface.Inthefinalstagesofcorticaldevelopment,synaptogenesisandapoptosisoccur.

•  Physically,themigrationofneuronsrequirethesamethreestepsnecessaryfor

migrationofanycell:Theextensionoftheleadingedgeofthelamellapodia

(mobilecellmembrane)thatexploresitsenvironmentforabractiveandrepulsive

signals,withthemovementofthenucleusintotheleadingprocess,andthe

retractionofthetrailingprocessasthecellmigrates.

•  Importantgenesidentifiedfromnaturallyoccurringcongenitaldisordersinmice

andhumansprovidedinsightintomolecularmechanismsofneuronalmigration:

•  RELNgene>reelermouse,whichhasdisruptedcerebellumandcerebralcortex

•  LIS1genemutationsleadtoformsoflissencephaly(smoothbrainwithnogyri)

Different‘modes’ofneuronal

migra5onoccur,andnotall

requireradialglia:

1.  RadialMigration

•  Somaltranslocation

•  Glialguidedmigration

2.  Tangentialmigration(oftenused

byneuronsmovingtothecortex

fromsubcorticalstructures)

What is Lissencephaly (LIS1) and Doublecortin (DCX) 

Lissencephaly(LIS1)

•  CompletelossofLIS1resultsinlethality,demonstratingthatLis1isanessentialgene.Thehumandisorder,IsolatedLissencephalySequence(ILS)isa

heterogeneousdisorderconsistingofvariablysevereLissencephaly,severe

cognitiveimpairmentandusuallyearlychildhooddeath.

•  MicewithvariousLis1alleleshavebeenproducedwithgradedreductioninLIS1dosage(expression).MicewithdecreasedlevelsofLis1exhibiteddosedependentdisorganizedcorticallayers,hippocampus,andolfactorybulb

becauseofneuronalmigrationdefects

Doublecortin(DCX)

•  AlthoughLIS1wasthefirstidentifiedhumangeneinvolvedinneuronal

migration,othershavesincebeenisolated.Oneofthese,doublecorHn(DCX),has

recentlybeenlinkedtoLIS1.

•  Mutationsanddele5onsofLIS1orDCX(alsoknownasXLIS)accountfor76%ofcasesofILS.RecentstudieshaveshownthatDCXbindstomicrotubules.

RELN

•  Reelermousehasseveregaitdisordersandneuronalmigra5ondeficitswithin

thecerebellumandcerebralcortex.

•  RELNisalargeextracellularmatrix(ECM)-likesecretedproteinproducedby

theCajal-Retziuscellswithintheouterlayersofcortex.RELNmayprovide

extracellularcuestoguideearlydevelopingneuronsalongaRELN-gradient

towardthepialsurface.

CDK5

•  Homozygousmicewithtargeteddisrup5onoftheserine–threoninekinase

Cdk5oritsregulatorysubunitp35alsodemonstrateseveredefectsincor5cal

lamina5on.

•  ThesimilarphenotypeofCdk5andRELNpathwaymutantssuggeststhatmany

oftheseproteinsparticipateinacommonsignaltransductionpathwaythatis

crucialforcor5callamination.ThoughCdk5KOmicedisplayareeler-like

phenotype,analysisoftheCdk5−/−mutantshasdemonstratedadistinct

differencefromreeler.Reelermutantshavedeficitsinearlyneuronmigration

andCdk5appearsmorecrucialformigrationoflater-bornneurons.

- studies from a naturally-occuring mouse mutant (the 'reeler' mouse)

- cortical histogenesis perturbed: lack of inside-out migration in the cortex-cortical layers are inverted. Progenitors fail to associate with radial glia. 

- mutation in the gene encoding reelin, a large glycoprotein, normally expressed in Cajal-Retzius cells (as an attractant?). 

- RELN also expressed by earlier cells which extend radially to pial surface at early stages called predecessor cells  

Shows migration route of the cells. Thye migrate out and to the surface of the cortex. What dictates this particular pattern to the cortex?

A lot of these cells are inhibitory neurons (GABA). inhibition is just as important as excitation. 

- Tangentially migrating interneurons express the homeodomain transcription proteins Dlx1 and Dlx2 9related to distal-less of Drosophila) 

- Absence of these transcription proteins results in failure of GAG -ergic interneurons to migrate to cortex and striatum. 

how they move up and around?

YOu can kO some TF proteins

If KO Dlx there will be no migration from the subcortex to the cortex. so it is this TF that mediate the movement. So how they guide it in terms of how they go> 

Note:mostmigratnginterneurons must bypassthestriatumeitherbyasuperficialroute(early)orbyadeeperroute(lateron).