ARL13B regulates Sonic Hedgehog signaling from outside primary cilia

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Abstract

ARL13B is a regulatory GTPase highly enriched in cilia. Complete loss of Arl13b disrupts cilia architecture, protein trafficking and Sonic hedgehog signaling. To determine whether ARL13B is required within cilia, we knocked in a cilia-excluded variant of ARL13B (V358A) and showed it retains all known biochemical function. We found that ARL13B^V358A protein was expressed but could not be detected in cilia, even when retrograde ciliary transport was blocked. We showed Arl13b^V358A/V358A mice are viable and fertile with normal Shh signal transduction. However, in contrast to wild type cilia, Arl13b^V358A/V358A cells displayed short cilia and lacked ciliary ARL3 and INPP5E. These data indicate that ARL13B's role within cilia can be uncoupled from its function outside of cilia. Furthermore, these data imply that the cilia defects upon complete absence of ARL13B do not underlie the alterations in Shh transduction, which is unexpected given the requirement of cilia for Shh transduction.

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All data generated or analysed during this study are included in the manuscript and supporting files.

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Eduardo D Gigante

Human Genetics, Emory University, Atlanta, United States

Competing interests
The authors declare that no competing interests exist.
Megan R Taylor

Human Genetics, Emory University, Atlanta, United States

Competing interests
The authors declare that no competing interests exist.
Anna A Ivanova

Biochemistry, Emory University, Atlanta, United States

Competing interests
The authors declare that no competing interests exist.
Richard A Kahn

Biochemistry, Emory University, Atlanta, United States

Competing interests
The authors declare that no competing interests exist.
Tamara Caspary

Human Genetics, Emory University, Atlanta, United States

For correspondence
tcaspar@emory.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-6579-7589

Funding

NINDS (R01NS090029)

Tamara Caspary

NIGMS (R35GM122549)

Tamara Caspary

NIGMS (R35GM122568)

Richard A Kahn

NINDS (T32NS096050)

Eduardo D Gigante

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were cared for in accordance with NIH guidelines and Emory's Institutional Animal Care and Use Committee (IACUC) under protocols DAR-2003545-072919N and PROTO201700587.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.