Non-canonical Hedgehog signaling regulates spinal cord and muscle regeneration in Xenopus laevis larvae

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Abstract

Inducing regeneration in injured spinal cord represents one of modern medicine's greatest challenges. Research from a variety of model organisms indicates that Hedgehog (Hh) signaling may be a useful target to drive regeneration. However, the mechanisms of Hedgehog signaling-mediated tissue regeneration remain unclear. Here we examined Hh signaling during post-amputation tail regeneration in Xenopus laevis larvae. We found that while Smoothened (Smo) activity is essential for proper spinal cord and skeletal muscle regeneration, transcriptional activity of the canonical Hh effector Gli is repressed immediately following amputation, and inhibition of Gli1/2 expression or transcriptional activity has minimal effects on regeneration. In contrast, we demonstrate that protein kinase A (PKA) is necessary for regeneration of both muscle and spinal cord, in concert with and independent of Smo respectively, and that its downstream effector CREB is activated in spinal cord following amputation in a Smo-dependent manner. Our findings indicate that non-canonical mechanisms of Hh signaling are necessary for spinal cord and muscle regeneration.

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

Article and author information

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Andrew M Hamilton

Physiology & Membrane Biology, University of California Davis, Sacramento, United States

For correspondence
andrewmichaelhamilton@gmail.com

Competing interests
The authors declare that no competing interests exist.
Olga A Balashova

Physiology & Membrane Biology, University of California Davis, Sacramento, United States

Competing interests
The authors declare that no competing interests exist.
Laura N Borodinsky

Physiology & Membrane Biology, University of California Davis, Sacramento, United States

For correspondence
lnborodinsky@ucdavis.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0003-2937-7023

Funding

National Science Foundation (1120796,1754340)

Laura N Borodinsky

National Institute of Neurological Disorders and Stroke (R01NS073055,R01NS105886,R01NS113859)

Laura N Borodinsky

Shriners Hospital for Children (86700-NCA)

Laura N Borodinsky

Shriners Hospital for Children (84303-NCA)

Andrew M Hamilton

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#20537) of the University of California Davis. This institution is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care, International (AAALAC). This institution has an Animal Welfare Assurance on file with the Office of Laboratory Animal Welfare (OLAW). The Assurance Number is A3433-01. All procedures were performed under tricaine anesthesia, and every effort was made to minimize suffering.

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.