NEUS 609 - Generation, Migration & Survival of Neural Cells II

inside-first outside-last

cortical cells obey an ____ program of neurogenesis

lissencephaly

spectrum of severe and rare brain malformations caused by defect in neuronal migration during embryonic development

• absence of infolding of cerebral cortex

• lower number of layers in cerebral cortex

• seizures, epilepsy, mental disability

radial migration

radial glia provides a scaffold for directed cell migration in developing brain

astrocytes

radial glial cells turn into ___ when neurogenesis is over and the scaffold they formed is no longer needed

extracellular factors

radial glial scaffold controlled by ____ from both apical/ventricular & basal/pial surfaces

embryonic cerebrospinal fluid

radial glia cells are anchored to the apical surface which give them access the ventricular lumen and the ____ which is where the extracellular factors/signals come from

• composition of the ___ changes over time during development

eCSF extracellular factors

• fibroblast growth factor (FGF2)

• insulin-like growth factor (IGF)

• transforming growth factor B1 (TGF-B1)

fibroblast growth factor

FGF2

maintains radial glia cell pool

insulin-like growth factor

IGF

increases glia cells proliferation

transforming growth factor B1

TGF-B1

triggers transition of radial glia cells into astrocytes

laminin

extracellular matrix component helping anchor radial glia cells’ processes into pial membrane

• part of glia limitans/pial surface

• binds to dystroglycan molecule in order to bind radial processes

dystroglycan

molecule bound to laminin which helps bind radial processes

• absence of this molecule causes cobblestone lissencephaly

cobblestone lissencephaly

condition due to the fact that neurons grow/migrate past the pial surface, past the glia limitans because dystroglycan molecules are absent

• leads to muscle eye brain disease (MEB) and Fukuyama congenital muscular dystrophy (FCMD)

reelin

molecule secreted by Cajal Retzius cells & promotes branching of radial glia cells in marginal zone, as well as maintains radial glia cell morphology

• binds to lipoprotein receptors ApoER2 & VLDLR on migrating neurons'

• stop signals inhibiting cell-cell recognition & adhesion

• absence of ___ causes disruption in the cortical layer organization

neural radial migration steps

1. extension of leading process driven by actin cytoskeletal dynamics

2. cytoplasmic swelling in leading process

3. invasion of cytoplasmic swelling by centrosome tethered to nucleus

4. progression of nucleus (nucleokinesis) which is regulated by microtubules dynamics

microtubule associated proteins

___ regulate neural migration

• PAFAH1B1/LIS1

• DCX

• NDEL1

tangential migration

movement of GABAergic interneurons from ganglionic eminences and basal ganglia to neocortex using transcription factors, chemo attractive cues, and motogenic factors

Sema 3A/3F

molecules preventing the improper interneurons invasion of developing striatum

chemoattractive cues

molecules like neuregulin 1 expressed in neocortex attracting the tangential migrating neurons

motogenic factors

molecules like Cxcl12 promoting interneuron motility

chain migration

neurons use neighboring neurons as substrate for migration

target dependent survival

• happens only in PNS

• neurotrophic theory

• neurons compete for target-derived survival factors that are limited

• survival factors inhibit the activation of apoptotic enzyme capase

1st peak of apoptosis

• happens in CNS

• target-independent cell death in neural progenitors and early post mitotic neurons

• controlled intrinsically and not determined by environment

• programmed cell death (PCD)

2nd peak of apoptosis

• happens in CNS

• PCD regulated by spontaneous activity (aka more active neurons survive) & brain derived neurotrophic factor (BDNF)

• inhibits apoptotic pathway like p53

• activates anti-apoptotic pathway like NF-kappaB or CREB