A calcineurin-mediated scaling mechanism that controls a K+-leak channel to regulate morphogen and growth factor transcription
Abstract
The increase in activity of the two-pore potassium-leak channel Kcnk5b maintains allometric juvenile growth of adult zebrafish appendages. However, it remains unknown how this channel maintains allometric growth and how its bioelectric activity is regulated to scale these anatomical structures. We show the activation of Kcnk5b is sufficient to activate several genes that are part of important development programs. We provide in vivo transplantation evidence that the activation of gene transcription is cell autonomous. We also show that Kcnk5b will induce the expression of different subsets of the tested developmental genes in different cultured mammalian cell lines, which may explain how one electrophysiological stimulus can coordinately regulate the allometric growth of diverse populations of cells in the fin that use different developmental signals. We also provide evidence that the post-translational modification of serine 345 in Kcnk5b by calcineurin regulates channel activity to scale the fin. Thus, we show how an endogenous bioelectric mechanism can be regulated to promote coordinated developmental signaling to generate and scale a vertebrate appendage.
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All data generated are included in the manscript and files
Article and author information
Author details
Funding
Deutsche Forschungsgemeinschaft (AN 797/4-1)
- Christopher L Antos
ShanghaiTech University
- Christopher L Antos
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Lilianna Solnica-Krezel, Washington University School of Medicine, United States
Ethics
Animal experimentation: This study was performed in strict accordance with guidelines for the care and use of laboratory animals for the European Union, Germany,Landesdirektion Sachsen, the Technische Universität Dresden, China and ShanghaiTech University. The protocols were approved by the Landesdirektion Sachsen (Permit number: DD24.1-5131/394/79) and the Shanghaitech Ethical Use of Aminals Committee (20200903003) All procedures using zebrafish were performed under Tricane anesthesia, and every effort was made to minimize discomfort and suffering.
Version history
- Received: July 3, 2020
- Accepted: April 7, 2021
- Accepted Manuscript published: April 8, 2021 (version 1)
- Version of Record published: May 10, 2021 (version 2)
Copyright
© 2021, Yi 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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Further reading
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We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibroblast growth factor (FGF) signaling in germ layer specification and head-to-tail development of Xenopus embryos. Here, we present an extracellular proteolytic mechanism involving this serpin-protease system in the developing neural crest (NC). Knockdown of SerpinE2 by injected antisense morpholino oligonucleotides did not affect the specification of NC progenitors but instead inhibited the migration of NC cells, causing defects in dorsal fin, melanocyte, and craniofacial cartilage formation. Similarly, overexpression of the HtrA1 protease impaired NC cell migration and the formation of NC-derived structures. The phenotype of SerpinE2 knockdown was overcome by concomitant downregulation of HtrA1, indicating that SerpinE2 stimulates NC migration by inhibiting endogenous HtrA1 activity. SerpinE2 binds to HtrA1, and the HtrA1 protease triggers degradation of the cell surface proteoglycan Syndecan-4 (Sdc4). Microinjection of Sdc4 mRNA partially rescued NC migration defects induced by both HtrA1 upregulation and SerpinE2 downregulation. These epistatic experiments suggest a proteolytic pathway by a double inhibition mechanism:
SerpinE2 ┤HtrA1 protease ┤Syndecan-4 → NC cell migration.
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- Developmental Biology
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