title: Gas1 is a receptor for sonic hedgehog to repel enteric axons.
abstract: 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 Gαi proteins that can couple with Smo, G protein α 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.
authors.affiliation: Department of Embryology, Carnegie Institution of Washington, Baltimore, MD 21218; and.
authors.forename: Shiying
authors.initials: S
authors.lastname: Jin
authors.affiliation: Department of Embryology, Carnegie Institution of Washington, Baltimore, MD 21218; and.
authors.forename: David C
authors.initials: DC
authors.lastname: Martinelli
authors.affiliation: Department of Embryology, Carnegie Institution of Washington, Baltimore, MD 21218; and.
authors.forename: Xiaobin
authors.initials: X
authors.lastname: Zheng
authors.affiliation: Rockefeller University, New York, NY 10065.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.affiliation: Department of Embryology, Carnegie Institution of Washington, Baltimore, MD 21218; and fan@ciwemb.edu.
authors.forename: Chen-Ming
authors.initials: CM
authors.lastname: Fan
mesh_terms: D000818:Animals; D001369:Axons / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D017615:Enteric Nervous System / Q000378:metabolism*; D058851:GPI-Linked Proteins / Q000378:metabolism; D044385:GTP-Binding Protein alpha Subunits / Q000378:metabolism; D053823:Hedgehog Proteins / Q000378:metabolism*; D007422:Intestines / Q000166:cytology; D051379:Mice; D009154:Mutation / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D000072086:Smoothened Receptor
chemical_list: D018797:Cell Cycle Proteins; D058851:GPI-Linked Proteins; D044385:GTP-Binding Protein alpha Subunits; C501180:Gas1 protein, mouse; C490964:Gnaz protein, mouse; D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; C465570:Shh protein, mouse; C491022:Smo protein, mouse; D000072086:Smoothened Receptor
keywords: Gas1; Hedgehog; axon guidance; chemorepellent; enteric neuron