Plexins promote hedgehog signaling through their cytoplasmic GAP activity
- University of Michigan-Ann Arbor, United States
Abstract
Hedgehog signaling controls tissue patterning during embryonic and postnatal development and continues to play important roles throughout life. Characterizing the full complement of Hedgehog pathway components is essential to understanding its wide-ranging functions. Previous work has identified Neuropilins, established Semaphorin receptors, as positive regulators of Hedgehog signaling. Neuropilins require Plexin co-receptors to mediate Semaphorin signaling, but a role for Plexins in Hedgehog signaling has not yet been explored. Here, we provide evidence that multiple Plexins promote Hedgehog signaling in NIH/3T3 mouse fibroblasts and that Plexin loss-of-function in these cells results in significantly reduced Hedgehog pathway activity. Catalytic activity of the Plexin GTPase activating protein (GAP) domain is required for Hedgehog signal promotion, and constitutive activation of the GAP domain further amplifies Hedgehog signaling. Additionally, we demonstrate that Plexins promote Hedgehog signaling at the level of GLI transcription factors and that this promotion requires intact primary cilia. Finally, we find that Plexin loss-of-function significantly reduces the response to Hedgehog pathway activation in the mouse dentate gyrus. Together, these data identify Plexins as novel components of the Hedgehog pathway and provide insight into their mechanism of action.
Data availability
All data generated or analyzed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institutes of Health (R01DC014428)
- Benjamin L Allen
National Institutes of Health (R01CA198074)
- Benjamin L Allen
National Institutes of Health (R01GM118751)
- Benjamin L Allen
National Institutes of Health (R01MH119346)
- Roman J Giger
National Institutes of Health (F31NS096734)
- Justine M Pinskey
National Institutes of Health (T32HD007505)
- Justine M Pinskey
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 housed in specific pathogen-free facilities at the University of Michigan. This study was approved by the University of Michigan Institutional Animal Care and Use Committee (IACUC; Protocol Number: PRO00010440).
Reviewing Editor
- Jeremy F Reiter, University of California, San Francisco, United States
Version history
- Received: October 15, 2021
- Preprint posted: December 16, 2021 (view preprint)
- Accepted: September 27, 2022
- Accepted Manuscript published: September 28, 2022 (version 1)
- Version of Record published: October 11, 2022 (version 2)
Copyright
© 2022, Pinskey et al.
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.
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Plexins promote hedgehog signaling through their cytoplasmic GAP activity
eLife 11:e74750.
https://doi.org/10.7554/eLife.74750
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