Enteric glia as a source of neural progenitors in adult zebrafish
- The Francis Crick Institute, United Kingdom
- University of Bath, United Kingdom
- AstraZeneca, United Kingdom
Abstract
The presence and identity of neural progenitors in the enteric nervous system (ENS) of vertebrates is a matter of intense debate. Here we demonstrate that the non-neuronal ENS cell compartment of teleosts shares molecular and morphological characteristics with mammalian enteric glia but cannot be identified by the expression of canonical glia markers. However, unlike their mammalian counterparts, which are generally quiescent and do not undergo neuronal differentiation during homeostasis, we show that a relatively high proportion of zebrafish enteric glia proliferate under physiological conditions giving rise to progeny that differentiate into enteric neurons. We also provide evidence that, similar to brain neural stem cells, the activation and neuronal differentiation of enteric glia are regulated by Notch signalling. Our experiments reveal remarkable similarities between enteric glia and brain neural stem cells in teleosts and open new possibilities for use of mammalian enteric glia as a potential source of neurons to restore the activity of intestinal neural circuits compromised by injury or disease.
Data availability
High-throughput sequencing data have been deposited in GEO under accession codes GSE145885.
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Expression analysis of adult zebrafish enteric nervous systemNCBI Gene Expression Omnibus, GSE145885.
Article and author information
Author details
Funding
The Francis Crick Institute (core funding)
- Vassilis Pachnis
BBSRC (BB/L022974/1)
- Vassilis Pachnis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Julia Ganz
Ethics
Animal experimentation: All animal experiments were carried out in compliance with the Animals (Scientific Procedures) Act 1986 (UK) and in accordance with the regulatory standards of the UK Home Office (Project Licence PCBBB9ABB). Experimental protocols were approved by the local Animal Welfare and Ethical Review Body (AWERB) of the Francis Crick Institute.
Version history
- Received: February 17, 2020
- Accepted: August 26, 2020
- Accepted Manuscript published: August 27, 2020 (version 1)
- Version of Record published: September 28, 2020 (version 2)
Copyright
© 2020, McCallum 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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Enteric glia as a source of neural progenitors in adult zebrafish
eLife 9:e56086.
https://doi.org/10.7554/eLife.56086
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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.
