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Organogenesis MCB141 part III Spring 2014 Lecture 4. spinal cord Neural tube formation: Previously- apical constriction, convergence-extension, elevation of neural folds, epiboly of the epidermis As the neural folds touch, they then fuse, and the neural tube segregates from the epidermis. Changes in cell adhesion contribute to the segregation of tissues: as mediated by cadherins (Gilbert6) Secondary neurulation and cavitation. 1. Primary neurulation is the process of rolling up of the neural tube from a sheet. However, this only occurs in the head and trunk of most vertebrates. The hollow neural tube forms by secondary neurulation in the posterior region, often also called the tailbud. Here cells proliferate as an apparently homogeneous mass, then segregate to form the nerve cord and somites (Gilbert6). Organization of differentiated cells 1.Neural crest cells form at the boundary of neural tube and epidermis (Gilbert6). These migrate widely through the embryo. In the head, they form the skull, and a variety of peripheral ganglia. In the trunk they form melanocytes, perpipheral neurons, and support cells (glia and schwann cells), some of the smooth muscle, endocrine cells (such as the adrenal medulla). 2.Anatomy of the spinal cord: During neurulation, the medial to lateral organization becomes ventral to dorsal. (see figure 1 from Chitnis et al). Types of neurons born in the neural tube: neural crest/ dorsal are sensory, intermediate are interneurons, ventral are motor neurons. 3.Larval vertebrates form primary neurons, and select them for differentiation using lateral inhibition, via the Notch pathway. (G8 161-163, Gilbert6 and discussion of juxtacrine signaling). 4.Amniotes have the same overall organization, but the sensory component is derived from neural crest, which migrates out and coalesces into the dorsal root ganglia (Gilbert6) How is the complexity of the spinal cord established? Embryological experiments implicate the notochord and surface ectoderm as signaling sources. Both grafting and deletion experiments have been used in intact embryos, or in explant culture. Medial/lateral become Ventral and dorsal signals; Sonic Hedgehog and BMPs are important signals in establishing the ventral to dorsal pattern. In the ventral neural tube, a morphogen gradient of SHH establishes different motor neuron types. Patterning of the spinal cord by opposing midline/ventral (notochord and floor plate) signals mediated by SHH and lateral/dorsal signals mediated by BMPs. 1. These signals set up different cell identities, which are important for the integration of neuronal activity. A diagram (not for memorization) shows the various cell types that arise from these domains this is also summarized in Gilbert. 2. The patterning of the spinal cord by Sonic Hedgehog (SHH) provides one of the best examples of a morphogen. The notochord and floorplate provide a localized source of SHH with diffusion of the ligand. Diffusion sets up a concentration gradient, which elicits multiple different cell fates (see picture). SHH has been shown to be present in a graded concentration. For a convincing view of SHH diffusion see figure 5 J, K (from Gritli-Linde et al) This has also been viewed more recently using a SHHGFP fusion protein (Figure 1J of Chamberlain et al. see supplementary figure for a diagram of the knockout) Is SHH a morphogen? 3. The signaling pathway is shown in Gilbert 6 , G8 page153. This pathway is unusual in that the primary receptor, patched, is a negative regulator of the pathway, inactivated by HH binding. In the last few years, differences in the vertebrate and invertebrate pathway have been found- in vertebrates, the Primary cilium acts an antenna for Hedgehog signals (see Ribes and Briscoe 4.Patched is also a target of the pathway, so once again, we see that an immediate effect of activation is the production of a negative feedback. 5. Explant assays using the intermediate neural tube can be used to document morphogen effectsillustrating the principle that SHH might work as a morphogen. Different doses cause development of Organogenesis MCB141 part III Spring 2014 Lecture 4. spinal cord floor plate, motor neurons etc. 6. Mutant studies in the mouse prove that SHH is required for ventral spinal cord fates, such as motor neurons. However, long range signaling from other hedgehog sources (IHH from the gut) contributes to signaling (adding to the evidence that HH can diffuse and act over a range). Elimination of the Hedgehog transducer Smoothened eliminates ventral fates. (from Wijgerde et al.) 7. Does SHH work directly as a morphogen, or might it set up a relay of signals? Use of chimeras between wild-type, and smo-/- SHH non-responsive cells (which should provide a SHH non-responsive “barrier” to a relay) proves that SHH can move over a distance as a morphogen, and is not activating a relay system. Dorsal fates occur in cells that cannot respond to SHH. Importantly, ventral fates result in cells beyond the “barrier” of smo-/-, and can even occur at distances larger than they usually would- this also shows that normal HH response soaks up the HH signal. This is because a response to HH is the induction of the HH receptor, patched. This illustrates the negative feedback property that hedgehog response normally restricts the range of SHH action. 8. How does the morphogen actually move? It has usually been assumed that the morphogen moves between cells by diffusion, but it may also move on long filopodia and be delivered directly to distant cells. 9. Different subtypes of neurons are marked by different constellations of transcription factors, these act in combination to determine cell fate. In the case of motor neurons, Olig2 is a primary determinant of motor neuron fate. 10. SHH causes a switch between gli repressor function and gli activator function (default proteolysis of the Gli transcription factors to make a repressor is prevented by activity of the Smo receptor (Gilbert 6) to establish graded activity of repressors in the ventral spinal cord. 11. At the dorsal side of the spinal cord, BMPs activate dorsal programs of gene expression. Just as in fly segmentation, the opposing action of repressors in the spinal cord establishes sharp boundaries. e.g. Pax6 vs Nkx2.2, Irx3 vs Olig2 (See p401 Gilbert7, 384 of G8 or the more up-to-date Figure 2 of this review for summary of cross repressive interactions. In the case of motor neurons, the domain is defined by olig2 expression. The domain is defined by the broad activator (activated Gli), and sculpted by localized repressors; dorsally by Irx3 repression, and ventrally by Nkx2.2 repression. Pattern emerges over time, with Pax6, then Olig2, then Nkx2.2 turned on