CSB331H1 Lecture 14: csb331 lecture 14

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University of Toronto St. George
Cell and Systems Biology
Maurice Ringuette

Somitogenesis and neural crest cell pathfinding - Lecture 14 Somitogenesis: somites bud off from unsegmented paraxial mesoderm Somitogenesis in chick embryo: • Somites bud off from the presomitic mesoderm (PSM) in an anterior to posterior in direction • Immature somite is mesenchymal. Then outer cells undergo MET to form an epithelial covering for each somite • Metameric pattern (segmented) • Somitomeres "whorls" of cells - precursors to being segmented Ectoderm and mesoderm partition simultaneously: • See somites forming as neurulation proceeds • Rostral to caudal direction ◦ Somites first in rostral then move towards caudal but they differentiate in opposite directions, so first born differentiate first • Number of somites is fixed (for a species) • Locations of fissures are predictable Somite Specification: • Somites are specified through inhibition of BMP signalling • Paraxial mesoderm expresses he BMP inhibition noggin, secreted from the notochord • If noggin secreting cells are placed transplanted into a region of prospective lateral plate, they re-specify that mesoderm, to form somites (detected by Pax3) ◦ Mesoderm is patterned by BMP gradient that increases laterally ◦ BMP signalling decreases from lateral plate mesoderm to neural tube Neural Creast Cell Guidance Repulsive Cues • There are NC cells in green and epithelial somites which begin to differentiate into sclerotome (first wave of differentiation), so somites become more cuboidal in shape and underneath there is dermamyotome • Eph & Npn2 receptors are two guidance cues that ensure neural crest cells migrate only through anterior portion of the sclerotome Spinal Cord Motor Neuron Pathfinding: • As with neural crest cells, motor neurone axons are inhibited from entering the posterior half of the sclerotome by repulsive cues, such as semaphornins and neuropilin/plexins • If you are looking at the neural tube as Sending seurons from the neural tube towards motor axons, they are also NC like in their ability to respond to guidance cues. Therefore, motor neurons will locate more in the ventral region and they will extend out ands connect to muscle in a segmented way NC derived phenotypes along the neural axis: • Enteric neural crest cells arise from the vagal (S1-S7) and lumbosacral (posterior to S28) region of the neural tube • NC cells can differentiate more than hundred of different cell types and they are responsible for ensuring that intestinal tracts are properly innervated which is critically dependent on NC cells From the sagal and sacral region of the neural tube to the gut: the longest migration distance by NCs in the embryo: • Glial-Derived Neurotrophic Factor (GDNF) from the gut mesenchyme: induce cell proliferation, directs cell migration and induces neural differentiation • The NC cells express the GDNF receptor Ret • Migrate at speed of between 35-40 um/h and takes about 3 weeks in humans - starting at week seven of gestation • An example of a neurocritopathy is Hirschsprung disease: ◦ Lower intestines cannot properly void solid resulting in large intestine (colon) obstruction or sever constipation. No NCs-derived ganglions and therefore cannot function ◦ Treatment: surgical removal of the segment of the large intestine lacking nerve cells, then connecting the healthy segment to the anus ◦ Mutations in Ret or GDNF • Other examples of neurocristopathies: ◦ Cleft palate: deficiency of mesencephalic NC cells, Melanoma, Congenital heart defect Colonization of the gut by neural crest cells: from the neurons and glia of the enteric nervous system: • The migration of neural crest-derived cells in the developing gut is revealed to a transgenic mouse embryo by the Cerulean Fluorescent protein, a marker of Phox2b expression • The TF Phox2b, a master regulator, guides development of the enteric nervous system, which controls motility and other functions of the gut • The NC cells that populate the enteric NS glow a vibrant blue-green • NC cells are populated in gastro intestinals, indicating NC cells contain Phox2b Semaphorins and Plexins • Semaphoring have different subclasses from 3,4,5,6 and 7 and they are diffusible • Sema3 ligand family is secreted • Neuropilin co-receptor required to bind Plexin A • Plexin receptors are structurally similar to Semaphorins • Homology to p120 Ras-GAP - you have two copies of it in plexus within the endodomain, so segmented Gaps and GTPases binding domain, so GAP will silence GTPase • Without a ligand, there will be a permissive cue and Sema3 • GTPase binding domain is quiescent which has no activity because GAP is silenced • When you have Sema3A, it interacts with neuropilin receptor, leading to activation of plexin receptor and as a result a conformational change. Other constitutively active monomeric GTPase RND1 will bind to GTPase binding domain and quiescent GAP becomes active again then R-Ras silences it which causes integrin not to become active • As diffusible Sema3A binds to neuropilin co-receptor it leads to the activation of plexin receptor and GAP, then promotes a constitutively active GTPase RND1 and GAP silences R- Ras • R-Ras gets inhibited and integirn does not bind to matrix anymore and becomes inactivated (No NC cell migration) • Summary: Without ligand, R-Ras is active, resulting in integrin-mediated attachment to the ECM. Semaphorin binding to neuropili
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