Migration and Axonal Pathfinding Flashcards
What do neural stem cells in the SVZ do?
proliferate to generate new neuroblasts
Where do neuroblasts migrate?
rostrally along the rostral migratory stream to the olfactory bulb
What are neuroblasts?
precursors of neurons during embryonic development
What do neural progenitor cells give rise to?
many glial and neuronal cell types of the CNS
What is neurogenesis?
the process by which new neurons are formed in the brain
What is gliogenesis?
the generation of glial cells (non-neuronal cells) in the nervous system
What happens to neurons generated by self-renewing neuroepithelial cells?
they are transformed into radial glial cells
What do radial glia cells produce?
intermediate progenitor cells and oligodendrocyte precursor cells (OPCs)
What do intermediate progenitor cells and OPCs produce respectively?
- intermediate progenitor = neurons
- OPCs = oligodendrocytes
What can radial glia become?
- astrcoytes
- astrocytic progenitors
- ependymal cells
What do type B cells in the cortical SVZ produce?
transit-amplifying cells (type C cells), which in turn produce OPCs and neurons
What is corticogenesis?
the process during which the cerebral cortex of the brain is formed
What does the neocortex comprise?
the largest part of the cerebral cortex and approximately half the volume of the human brain
What is the neocortex responsible for?
the neuronal computations of attention, thought, perception and episodic memory
How many layers does the neocortex have?
6 (I is most superficial and VI is the deepest)
What is the pial surface of the brain?
the interface between the surface of the brain and the surrounding meninges
What are the 2 major cortical neuronal populations?
- cortical projection neurons
- cortical interneurons
What are cortical projection neurons and where do they come from?
excitatory in nature (glutamatergic) that account for ~80% of all cortical neurons that come from cortical proliferative areas
How do cortical projection neurons migrate?
radially to the cortical plate through the intermediate zone
What are cortical interneurons and where do they come from?
inhibitory in nature (GABAergic) that come from the medial ganglionic eminence
What can cortical interneurons do?
mediate feedforward inhibition, feedback inhibition, volume transport, and disinhibition
What are the 2 modes of cortical interneuron migration?
- radial (follow a track that is perpendicular to the neuroepithelial surface)
- tangential (parallel to the pial surface)
What is Somal translocation mediated by?
MTs in the neuron
What are the 3 steps of somal translocation?
- leading process extends as driven by MT extension
- centrosome moves forward into the leading process while trailing end of the cell contracts
- nucleus moves forward toward the centrosome and the trailing process retracts
What is radial migration mediated by?
the radial glia during locomotion
What are the 5 steps of radial migration?
- generation of newborn cortical neurons
- multipolar tangenital migration
- multipolar-unipolar transition
- attachment and locomotion
- detachment
What are cadherins?
calcium dependent homophilic molecules
What does N-cadherin do during corticogenesis?
facilitate radial migration by enabling cell-to-cell adhesion between migrating neurons and radial glial fibres
What is cortical migration coordinated by?
- intrinsic factors e.g. actins, tubulins, RhoA, dynein, myosin II
- extrinsic factors e.g. Reelin, ephrins, RA, Wnt
How do the extrinsic and intrinsic factors that control cortical migration affect the cytoskeleton?
by binding to cell surface receptors to induce changes e.g. polymerisation of tubulin and actin
What is Reelin?
a secreted ECM glycoprotein produced by Cajal-Retzius cells in the marginal zone that promotes migration along and/or detachment from radial glia cells
What do migrating neurons express?
Reelin receptors ApoER2 (Apolipoprotein E receptor 2) and VLDLR (Very low-density lipoprotein receptor)
What is a key adaptor protein in Reelin signalling?
Disabled-1 (Dab1)
What have autosomal recessive mutations in the RELN gene been linked to?
developmental disorder Lissencephaly 2 with brain malformation
What does neuronal maturation lead to?
neuronal polarisation
What is neuronal polarisation?
the formation of axons and the separation of the axonal and somatodendritic domains
What is axonal pathfinding?
the process of how an axon finds its target
What are the 2 principal events that take place in the in vitro system of axonal pathfinding?
- growth of neurites
- establishment of neuronal polarity
What are the 5 steps of neuronal differentiation in vitro?
- neuritogenesis
- neurite outgrowth
- pathfinding
- targeting
- synaptogenesis
Where does neuritogenesis occur during neuronal differentiation?
at thin, actin rich peripheral protrusions surrounding the soma
What drives neurite outgrowth and pathfinding?
the growth cone (tip of the axon)
What are the 2 domains of the growth cone?
- central (C) domain that contains MTs
- peripheral (P) domain that contains F-actin in filopodia and lamellipodia
What are filopodia and lamellopodia made up of respectively?
- filopodia = bundles of longer F-actin
- lamellipodia = randomly oriented networks of shorter F-actin between the filopodia
What is the assembly and disassembly of F-actin orchestrated by?
a variety of actin-binding proteins that function downstream of Rho-family GTPases
What does profilin do?
promote actin assembly at the barbed end
What is CapZ?
a barbed-end capping protein that prevents F-actin elongation
What is WASP/Scar?
activator of Arp2/3 complex
What does the Arp2/3 complex do?
initiate new F-actin as a branch on the side of an existing filament
What does ADF/cofilin do?
stimulate F-actin depolymerisation and debranching at the pointed end (actin severing protein)
What regulates actin dynamics during neuritogenesis?
LIM kinase 1 and cofilin
What does an increase in intracellular cAMP conc by activation of AC trigger?
- increased LIM kinase 1 expression
- novel expression of VDCCs
What are the effects of an increase in LIM kinase 1?
- cofilin phosphorylation which abolishes its ability to bind and depolymerise actin
- this promotes polymerisation of actin monomers which induces neuritogenesis
What does novel expression of VDCCs do?
- negatively regulate LIM kinase 1 expression which induces cofilin dephosphorylation i.e. inhibition of neuritogenesis
- increase intracellular Ca2+ in response to membrane depolarisation
What do commissural axons in drosophila do?
cross the midline once due to Comm being switched on
Where is Comm switched off?
in ipsilateral neurons and post-crossing commissural neurons
What does Comm do and how?
regulate the sensitivity of axons to the midline repellent Slit by controlling the intracellular trafficking of Robo, the slit receptor
What are the 4 major families of axonal instructive guidance cues and receptors?
- netrin/UNC-5/DCC
- slit/Robo
- ephrin/Eph receptor
- semaphorin/semaphorin receptors
What activates and inactivates Rho GTPases respectively?
- GEF (guanine nucleotide exchange factor) activates
- GAP (GTPase activating protein) inactivates
Give an example of guidance cue signalling
growth cone collapse caused by semaphorins
What does combinatorial assembly of semaphoric receptors do?
increase the diversity of ligands to which a family of guidance receptors can respond
What can addition of UNC-5 subunits to a DCC receptor complex do?
convert the guidance response from attractive to repulsive
