Primary Cilia Signaling Promotes Axonal Tract Development and Is Disrupted in Joubert Syndrome-Related Disorders Models

• Type of Material: Article
• Authors: Jiami Guo, University of North Carolina; James Otis, University of North Carolina; Sarah K. Suciu, Emory University; Christy Catalano, University of Calgary; Lei Xing, University of North Carolina; Sandii Constable, Emory University; Dagmar Wachten, University of Bonn; Stephanie Gupton, University of North Carolina; Janice Lee, University of North Carolina; Amelia Lee, University of North Carolina; Katherine H. Blackley, University of North Carolina; Travis Ptacek, University of North Carolina; Jeremy M. Simon, University of North Carolina; Stephane Schurmans, University of Liege; Garret D. Stuber, University of Washington; Tamara Caspary, Emory University; E.S. Anton, University of North Carolina
• Language: English
• Date: 2019-12-16
• Publisher: CELL PRESS
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2019
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.devcel.2019.11.005
• Title of Journal or Parent Work: DEVELOPMENTAL CELL
• Volume: 51
• Issue: 6
• Start Page: 759
• End Page: +
• Grant/Funding Information: This research was supported by NIH grant NS090029 to EA and TC, Natural Sciences and Engineering Research Council of Canada grant RGPIN-2019-04820 to JG, F31 NS101806 and T32GM008490 to SKS, and the confocal imaging core of NINDS grant 5P30NS045892. We thank A. Kolodkin and A. S. LaMantia for helpful comments.
• Keywords: DYNAMICS; MEMBRANE; ADENYLYL-CYCLASE; ARL13B VARIANT; NEURONAL PRIMARY CILIA; Science & Technology; PATHWAY; MUTATIONS; Developmental Biology; INPP5E; TRAFFICKING; PROTEIN-COUPLED RECEPTORS; Life Sciences & Biomedicine; Cell Biology
• Research Categories: Biology, General; Biology, Cell

Abstract

Appropriate axonal growth and connectivity are essential for functional wiring of the brain. Joubert syndrome-related disorders (JSRD), a group of ciliopathies in which mutations disrupt primary cilia function, are characterized by axonal tract malformations. However, little is known about how cilia-driven signaling regulates axonal growth and connectivity. We demonstrate that the deletion of related JSRD genes, Arl13b and Inpp5e, in projection neurons leads to de-fasciculated and misoriented axonal tracts. Arl13b deletion disrupts the function of its downstream effector, Inpp5e, and deregulates ciliary-PI3K/AKT signaling. Chemogenetic activation of ciliary GPCR signaling and cilia-specific optogenetic modulation of downstream second messenger cascades (PI3K, AKT, and AC3) commonly regulated by ciliary signaling receptors induce rapid changes in axonal dynamics. Further, Arl13b deletion leads to changes in transcriptional landscape associated with dysregulated PI3K/AKT signaling. These data suggest that ciliary signaling acts to modulate axonal connectivity and that impaired primary cilia signaling underlies axonal tract defects in JSRD.