期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：1
页码：E73-E80
DOI：10.1073/pnas.1418629112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe enteric nervous system is the largest peripheral nervous subsystem. Enteric axons form a tubular meshwork arborizing the smooth muscles of the digestive tract to control gut movement. Deficiencies of enteric neurons cause megacolon and constipation--that is, Hirschsprung's disease. How enteric axons are kept in the smooth muscle layers without projecting toward the gut epithelium is unknown. We provide, to our knowledge, the first insights into how these axons are confined to the periphery and, in the process, define a novel mechanism of sonic hedgehog signaling for axon repulsion involving the guidance receptor growth arrest specific gene 1 and the signaling G protein z. We believe this to be a conceptual advance in understanding a key topological problem in axonal arborization and to have important health implications. The myenteric plexus of the enteric nervous system controls the movement of smooth muscles in the gastrointestinal system. They extend their axons between two peripheral smooth muscle layers to form a tubular meshwork arborizing the gut wall. How a tubular axonal meshwork becomes established without invading centrally toward the gut epithelium has not been addressed. We provide evidence here that sonic hedgehog (Shh) secreted from the gut epithelium prevents central projections of enteric axons, thereby forcing their peripheral tubular distribution. Exclusion of enteric central projections by Shh requires its binding partner growth arrest specific gene 1 (Gas1) and its signaling component smoothened (Smo) in enteric neurons. Using enteric neurons differentiated from neurospheres in vitro, we show that enteric axon growth is not inhibited by Shh. Rather, when Shh is presented as a point source, enteric axons turn away from it in a Gas1-dependent manner. Of the Gi proteins that can couple with Smo, G protein Z (Gnaz) is found in enteric axons. Knockdown and dominant negative inhibition of Gnaz dampen the axon-repulsive response to Shh, and Gnaz mutant intestines contain centrally projected enteric axons. Together, our data uncover a previously unsuspected mechanism underlying development of centrifugal tubular organization and identify a previously unidentified effector of Shh in axon guidance.
