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

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.

journal_name

Dev Cell

journal_title

Developmental cell

authors

Guo J,Otis JM,Suciu SK,Catalano C,Xing L,Constable S,Wachten D,Gupton S,Lee J,Lee A,Blackley KH,Ptacek T,Simon JM,Schurmans S,Stuber GD,Caspary T,Anton ES

doi

10.1016/j.devcel.2019.11.005

subject

Has Abstract

pub_date

2019-12-16 00:00:00

pages

759-774.e5

issue

6

eissn

1534-5807

issn

1878-1551

pii

S1534-5807(19)30936-0

journal_volume

51

pub_type

杂志文章

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