The Ciliary Protein Arl13b Functions Outside of the Primary Cilium in Shh-Mediated Axon Guidance

• Type of Material: Article
• Authors: Julien Ferent, Montreal Clinical Research Institute; Sandii Constable, Emory University; Eduardo D. Gigante, Emory University; Patricia T. Yam, Montreal Clinical Research Institute; Laura E. Mariani, Emory University; Emilie Legue, Yale School of Medicine; Karel F. Liem, Yale School of Medicine; Tamara Caspary, Emory University; Frederic Charron, Montreal Clinical Research Institute
• Language: English
• Date: 2019-12-10
• Publisher: Elsevier (Cell Press): OAJ
• Publication Version: Final Published Version
• Copyright Statement: © 2019 The Author(s)
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.celrep.2019.11.015
• Title of Journal or Parent Work: Cell Reports
• ISSN: 2211-1247
• Volume: 29
• Issue: 11
• Start Page: 3356
• End Page: +
• Grant/Funding Information: J.F. was supported by Fondation pour la Recherche Médicale (FRM); FRQS; and CIHR post-doctoral fellowships.; Work performed in the T.C. laboratory was supported by funding from NIH grants R01GM110663, R01NS090029, and R35GM122549.; E.D.G. was supported by NIH training grant T32NS096050; L.E.M. was supported by NIH training grants (GM08605 and EY007092) and an American Heart Association pre-doctoral fellowship (11PRE7200011).; Work performed in the F.C. laboratory was supported by funding from the Canadian Institutes of Health Research (CIHR FDN334023); the Fonds de Recherche du Québec - Santé (FRQS); and the Canada Foundation for Innovation (CFI 33768).; Further support came from the Emory University Integrated Cellular Imaging Microscopy Core of the Emory Neuroscience NINDS Core Facilities grant P30NS055077.
• Keywords: RESPONSIVENESS; FAMILY; JOUBERT SYNDROME; Life Sciences & Biomedicine; Cell Biology; MUTATIONS; HEDGEHOG GUIDES AXONS; SONIC HEDGEHOG; REQUIRES; Science & Technology; NETRIN-1; REPULSION; ROOF PLATE
• Research Categories: Biology, Genetics; Biology, Neuroscience; Biology, Cell

Abstract

The small GTPase Arl13b is enriched in primary cilia and regulates Sonic hedgehog (Shh) signaling. During neural development, Shh controls patterning and proliferation through a canonical, transcription-dependent pathway that requires the primary cilium. Additionally, Shh controls axon guidance through a non-canonical, transcription-independent pathway whose connection to the primary cilium is unknown. Here we show that inactivation of Arl13b results in defective commissural axon guidance in vivo. In vitro, we demonstrate that Arl13b functions autonomously in neurons for their Shh-dependent guidance response. We detect Arl13b protein in axons and growth cones, far from its well-established ciliary enrichment. To test whether Arl13b plays a non-ciliary function, we used an engineered, cilia-localization-deficient Arl13b variant and found that it was sufficient to mediate Shh axon guidance in vitro and in vivo. Together, these results indicate that, in addition to its ciliary role in canonical Shh signaling, Arl13b plays a cilia-independent role in Shh-mediated axon guidance.