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Mariani LE, Bijlsma MF, Ivanova AA, et al. Arl13b regulates Shh signaling from both inside and outside the cilium. Mol Biol Cell. 2016;doi: 10.1091/mbc.E16-03-0189.
Mariani, L. E., Bijlsma, M. F., Ivanova, A. A., Suciu, S. K., Kahn, R. A., & Caspary, T. (2016). Arl13b regulates Shh signaling from both inside and outside the cilium. Molecular biology of the cell, . https://doi.org/10.1091/mbc.E16-03-0189
Mariani, Laura E, et al. "Arl13b regulates Shh signaling from both inside and outside the cilium." Molecular biology of the cell vol. (2016). doi: https://doi.org/10.1091/mbc.E16-03-0189
Mariani LE, Bijlsma MF, Ivanova AA, Suciu SK, Kahn RA, Caspary T. Arl13b regulates Shh signaling from both inside and outside the cilium. Mol Biol Cell. 2016 Sep 28; doi: 10.1091/mbc.E16-03-0189. Epub 2016 Sep 28. PMID: 27682584; PMCID: PMC5170560.
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Mol Biol Cell. 2016 Sep 28; doi: 10.1091/mbc.E16-03-0189. Epub 2016 Sep 28.

Arl13b regulates Shh signaling from both inside and outside the cilium.

Molecular biology of the cell

Laura E Mariani, Maarten F Bijlsma, Anna A Ivanova, Sarah K Suciu, Richard A Kahn, Tamara Caspary

Affiliations

  1. *Department of Human Genetics, Emory University, Atlanta, GA, USA Neuroscience Graduate Program, Emory University, Atlanta, GA, USA.
  2. Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Academic Medical Center and Cancer Center Amsterdam, Amsterdam, The Netherlands.
  3. Department of Biochemistry, Emory University, Atlanta, GA, USA.
  4. *Department of Human Genetics, Emory University, Atlanta, GA, USA Genetics and Molecular Biology Graduate Program, Emory University, Atlanta, GA, USA.
  5. *Department of Human Genetics, Emory University, Atlanta, GA, USA [email protected].

PMID: 27682584 PMCID: PMC5170560 DOI: 10.1091/mbc.E16-03-0189

Abstract

The regulatory GTPase Arl13b localizes to primary cilia, where it regulates Sonic hedgehog (Shh) signaling. Missense mutations in ARL13B can cause the ciliopathy Joubert syndrome, while the mouse null allele is embryonic lethal. We used mouse embryonic fibroblasts as a system to determine the effects of Arl13b mutations on Shh signaling. We tested a total of seven different mutants, three JS-causing variants, two point mutants predicted to alter guanine nucleotide handling, one that disrupts cilia localization, and one that prevents palmitoylation and thus membrane binding, in assays of transcriptional and non-transcriptional Shh signaling. We found that mutations disrupting Arl13b's palmitoylation site, cilia localization signal, or GTPase handling altered the Shh response in distinct assays of transcriptional or non-transcriptional signaling. In contrast, JS-causing mutations in Arl13b did not affect Shh signaling in these same assays, suggesting these mutations result in more subtle defects, likely affecting only a subset of signaling outputs. Finally, we show that restricting Arl13b from cilia interferes with its ability to regulate Shh-stimulated chemotaxis, despite previous evidence that cilia themselves are not required for this non-transcriptional Shh response. This points to a more complex relationship between the ciliary and non-ciliary roles of this regulatory GTPase than previously envisioned.

© 2016 by The American Society for Cell Biology.

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