The enteric nervous system plays a critical role in normal function of the intestine. Enteric neurons provide motor and sensory information to generate propulsive movement and maintain organ homeostasis. Enteric neurons originate from neural crest cells, migrate to the rostral portion of the digestive system, enter the outer mesenchyme, and migrate to the caudal end. Along the way, the enteric precursors proliferate and differentiate into neurons and glia thereby innervating the entire organ. The critical nature of enteric neuron innervation of the intestine is demonstrated by Hirschsprung's disease. This digestive disease occurs in 1 in 5000 live births and results in aganglionic segments of the human colon. The length of aganglionic intestinal segments varies due to multiple genetic abnormalities that give rise to the disease. Genes responsible for development of the enteric neurons are strongly conserved across multiple vertebrate species, including zebrafish. Genetic conservation combined with conservation of structure and function of the vertebrate digestive system makes animal models like zebrafish an effective model to study the genetics of enteric and smooth muscle development. We will use zebrafish to determine additional genetic components underlying migration and differentiation of enteric precursors and development of smooth muscle. Previous investigations have determined that enteric neurons develop using homologous pathways that have been identified in other model systems.
Specific aim1 will identify the wild type pattern of enteric proliferation and neuronal subtype differentiation.
Specific aim 2 tests the hypothesis that the zebrafish homologue of zFKBP/SMAP and BMP signaling are critical for development of enteric and intestinal smooth muscle.
Specific aim 3 tests the hypothesis that the enteric and intestinal smooth muscle defects in digestive mutants flotte latte(flo) and slimjim (slj) are due in part to identified homologous signaling pathways. These experiments will lead to a more complete understanding of the genetics of enteric and smooth muscle development and the components that underlie Hirschprung's disease. ? ? ?
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