Developmental Neurobiology
L1 | Molecular Mechanisms of Brain Development
Mention main structures important for neural tube formation
Gastrulation: invagination of blastocyst
Start layering of germ layers: CNS cells need to be inhibited from becoming skin
Mesoderm: skeletal, muscular and cardiovascular systems
Endoderm: urinary, digestive and respiratory systems
Ectoderm: skin (epidermis), and nervous system
Neurulation: induction of neural tissue
1. Neural plate folding forms neural tube ectoderm (CNS)
2. Neural tube formation (brain and spinal cord)
o Inductive signals from non-neuronal epidermis (grey)
o Notochord: vertebral column; secretes inhibiting factors, like inhibiting skin
formation & regional specialization
3. Neural crest cells leave the ectoderm (peripheral nervous system, red)
Spina bifida: failure to close the neural tube posteriorly; can often be repaired
Multi-factorial (>300 genes in mice cause NTDs)
Familial forms caused by mutations in VANGL1 and 2 genes
o These receptors are present on all cells of your body!!
Folic acid (Vit. B9) deficits are causally related to neural tube defects
o When you give Vit. B9 to pregnant women, it seems to make the PCP
pathway more efficient and prevents spina bifida
o Vit. B9 treatment in cultures has an effect of DNA methylation
could this be mechanism?
Explain BMP4 signalling
BMP4: secreted molecule that when bound to the ectoderm leads to skin formation
However, the notochord secretes BMP4 inhibitors like chordin, noggin and follistatin that block the effect of
BMP4 and allow formation of neural tissue.
Noggin/chordin double KO: skin formation instead of brain, also no eyes
Describe major signalling molecules that control A/P patterning
Hensen’s node: organizer identified by Hans Spemann in chickens that he called mesodermal signaling centers.
It organizes D/V and A/P patterning and induce neural tissue from ectoderm.
Transplant the organizer in chicken induces secondary neuraxis
Transplant the organizer from quail to chicken formation second neural tube
Gradients of secreted glycoproteins pattern the nervous system A/P
Chopped up notochord and did RNA processing found differential expression
1
, PA
=> FGF, Wnt and RA induce posterior identity
AP
=> inhibitors of these molecules induce anterior
identity
Describe major signalling molecules that control D/V patterning
Gradients of BMP4 and Shh provide D/V inductive signals Antagonism of BMP4 and Shh!
this is past defining the ectoderm
BMP4 by roofplate binds to different receptors
Sonic hedgehog (Shh) secreted by notochord
Shh expression controls ventral patterning via concentration dependent repression of specific TFs
Describe origin and fate of neural crest cells
Neural crest cells: migrate from ectoderm and give rise to various cell types; unique for vertebrates
All NCC come from the same stem cells
Depending on where they come from they become
o Neurons & glia of PNS
o Pigment cells
o Facial cartilage & bone
When something goes wrong with this it’s called neurocristopathies
Chicken neural crest migration during closure of neural tube they leave and find their way in the body
2
, L2 | Neuronal Migration
Describe mammalian cortical layering
New cells born in ventricular zone (VZ) neuroepithelium
1 mother cell produces ≈ 10,000 daughter cells
‘All’ most neurons are produced prenatally
Rate of proliferation extremely high;
thousands/minute
Cell proliferation:
Cortical neurons are formed by a-symmetrical
divisions in the VZ
Notch-1 and Numb play a role
Cell migration:
1. Post-mitotic neurons migrate from ventricular zone move a lot
2. Migrating neurons are structurally and functionally immature
3. Once at their destination, specific genes are activated inducing growth of axons, dendrites, and synapses
(polarization)
Cortical layering: 6 layers in the cortex
“Inside out”: old neurons in layer 6
o Neurons generated in the VZ move to their final destination in an inside out manner
o Explained by birth dating!!
Explain different modes of migration
Two modes of trafficking of cells coming from the VZ towards the cortex layers
Somal translocation during early corticogenesis
Glia-guided migration at later stages (radial migration) --> more efficient
Time-lapse imaging showed that the neurite attaches to the cortex surface and that then the
soma is pulled up afterwards
Also showed that neurons align with radial glial cells and move along these cells towards their
final destination
There is migration from bottom to top (radial), but also from the bottom to the side (tangential)
Explain cellular birth-dating
Birth-dating studies: proof the inside-out layering of the cortex
Neurons born first close to VZ
Younger neurons move to layer 1
3
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