20-P002 Pre-enteric migration of sacral neural crest cells is affected in Dominant megacolon embryos

The posterior lateral line primordium (pLLp) migrates caudally and periodically deposits neuromasts under the skin in the zebrafish trunk and tail. Each neuromast, formed within the migrating pLLp, has a central atoh1-positive hair cell determined by Notch mediated-lateral inhibition. The generation of new neuromasts and their deposition as the pLLp migrates caudally is coordinated by mutually antagonistic signaling centers; a Wnt signaling center at the leading edge and a FGF signaling center in the adjacent trailing domain, which determines both the morphogenesis of epithelial rosettes and expression of atoh1 in the forming neuromasts. We have now shown that the central atoh1 expressing cell in the neuromast also plays a critical role in regulating FGF signaling. When Notch signaling fails, too many cells express atoh1 and this eventually leads to failure of FGF signaling and unregulated Wnt signaling. This eventually leads to collapse and disorganization of the migrating pLLp. Computational modeling reveals how interaction between these three signaling systems and differential regulation of chemokine receptors regulates morphogenesis and migration of the pLLp. The modeling also predicts a key role played by negative feedback in the self-organization of this remarkable system.