Neural Development - Patterning of nervous system, migration of immature neurons into their final position Flashcards
How does Anterior - Posterior Polarity of the Neural Tube occur?
Formation of neural tube
= does NOT occur all at once along full length
= it begins in the middle at embryonic day 20 in humans
(then continues towards each end)
= openings left at each end are called the anterior (cranial) and posterior (caudal) neuropores
= anterior neuropore closes on day ~25
= posterior neuropore closes on day ~27
Somites
= balls of mesoderm that mature into the segmented axial skeleton
= each pair is added sequentially from head to tail down the length of the embryo
How is Wnt signalling (last slide deck) involved in neural patterning?
Wnt inhibitors
= e.g. Dickkopf, Cerberus, Frzb, IGF
= made by dorsal anterior mesoderm and the organiser
Wnt
= involved in formation of anterior/posterior and dorsal/ventral structures in the early nervous system
= ‘neural patterning’
Wnt gradient
= highest at posterior / ventral axes
= controls development of the nervous system
(paracrine factor antagonists)
(In Xenopus)
= ectopic placement of cerebrus during early gastrulation gives rise to a secondary head structure
How are FGF and RA also involved in Anterior-Posterior Patterning?
FGF
= Fibroblast Growth Factor
= made at posterior
= degraded at anterior
RA = Retinoic Acid
= made by central mesoderm
FGF, RA, Wnt signalling
= all regulate Hox gene expression
Unique Hox at each segment
= specifies its anterior-posterior identitu
What are the gradients controlling Dorso-Ventral Patterning?
Dorsal
= sensory neurons
Ventral
= motor neurons
= involves Wnt inhibitors, TGFβ family and Shh
How does brain develop from the neural tube?
Anterior part of neural tube
= divides rapidly to form 3 primary vesicles:
= forebrain (prosencephalon)
= midbrain (mesencephalon)
= hind brain (rhombencephalon)
Part of forebrain (telencephalon)
= curls up and around = becomes cerebral cortex
Posterior part = forms spinal chord
What do the 3 primary brain vesicles form in adult brain?
Forebrain
= primarily cerebral cortex, underlying white matter, corpus callosum, basal ganglia
Midbrain
= vision, hearing, motor control, sleep/wake, arousal (alertness), temperature regulation
Hindbrain
= Medulla
(autonomic functions of breathing, heart rate, blood pressure)
= Pons
(part of brainstem, relays signals from forebrain to cerebellum, deals with sleep, respiration, swallowing, bladder control, hearing, equilibrium, taste, eye movement, facial expressions, facial sensation)
= Cerebellum
(posture, balance)
How are the brain layers structured?
e.g. Cerebral cortex
= made of many layers
= different cell types in different layers
= orientation of neurons are very ordered
= neurons migrate on radial glial cell processes
What is the “Inside Out” sequence?
= formed by cortical layers
- First cohort of post-mitotic neurons moves from the ventricular zone towards the pial surface to form the preplate
- The first migration wave of cortical plate neurons arrives in the middle of preplate
= splitting it into 3 zones
(marginal zone, cortical plate, subplate) - More coritcal plate neurons arrive in an ‘inside out’ sequence
= with earliest born neurons destined to become future layer 6
= last- born to become future layer 2
How to visualise neurons?
= use intermediate filament proteins and cell markers
Neural stem cells
= express nestin during early stages of development in CNS and PNS
(intermediate filament protein)
Upon differentiation
= nestin becomes downregulated and is replaced by cell specific intermediate filament proteins
Immature glial cells
= (including radial glial cells)
= express vimentin
Mature nerve cells
= express neurofilament proteins
(NF-H, NF-M, NF-L)
Mature glial cells
= express glial fibrillary acidic protein (GFAP)
= these intermediate filament proteins can be used as cell-specific markers in neural developmental studies
How do neurons migrate?
Migrating neurons
= detach from radial glia
= then can translocate tangenitally to their final positions
Permissive factors (cortical plate)
= tell neuron to migrate sideways to final position
Restrictive factors (subpial zone)
= tell neuron to stop migrating upwards
What is Reelin?
= important for cortical development
= an exracellualr matrix-associated glycoprotein
Cajal-Retzius cells
= in marginal zone
= light up when the developing mouse brain cortex is immunostained with antibody to reelin
= have ascending processes that contact pial surface and a horizontal axon plexus
= they secrete ‘reelin’ = essential for neuronal migration
What are Reelin Receptors?
Reelin binds to:
= very low density lipoprotein receptor (VLDL-R)
= apolipoprotein E receptor type 2 (ApoER2)
= amyloid precursor protein (APP)
= integrin receptors
Rest of the process
= involves signalling molecules
(many of which identified in mutant mice)
Disabled 1 (Dab1)
= binds to cytoplasmic tail or receptors above + becomes phosphorylated
(possible exception of integrin)
Downstream signalling cascades
= result in changes in gene expression and surface properties of neuron causing them to migrate
= therefore detach from glial cells - stop moving upwards
What was found in Reeler Null and Scrambler (Dab1 NULL) mice?
Staining for chondroitin sulfate proteoglycans (above) labels preplate neurons
In normal mice
= preplate neurons are split into the margical zone, cortical plate and subplate
In both reelin null and scrambler (Dab1 null) mice
= pleplate fails to split
= because new neurons are unable to penetrate it
= scrambler does not have Dab1 and so cannot respond to Reelin signal
= human reelin mutation has been linked to lissencephaly (lack of brain folds, fatal) and increased chance of autism
What are adult neural stem cells?
Some stem cells retained in the human brain
e.g. the dendate gyrus of hippocampys (subgranular zone)
= ? involved in memory
e.g. lining of lateral ventricles (subcentricular zone)
= move to olfactory bulb
