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Inhibition of the serine protease HtrA1 by SerpinE2 suggests an extracellular proteolytic pathway in the control of neural crest migration

Pera, Edgar M. LU ; Nilsson De Moura, Josefine ; Pomeshchik, Yuriy LU orcid ; Roybon, Laurent LU and Milas, Ivana LU (2023) In eLife 12.
Abstract

We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibro-blast 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... (More)

We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibro-blast 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 endog-enous 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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
eLife
volume
12
article number
RP91864
publisher
eLife Sciences Publications
external identifiers
  • pmid:38634469
  • scopus:85192531103
ISSN
2050-084X
DOI
10.7554/eLife.91864
language
English
LU publication?
yes
id
33f1f3e0-8591-4125-b426-7aba5b47bd4d
date added to LUP
2024-05-30 14:59:46
date last changed
2024-06-13 15:55:01
@article{33f1f3e0-8591-4125-b426-7aba5b47bd4d,
  abstract     = {{<p>We previously showed that SerpinE2 and the serine protease HtrA1 modulate fibro-blast 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 endog-enous 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.</p>}},
  author       = {{Pera, Edgar M. and Nilsson De Moura, Josefine and Pomeshchik, Yuriy and Roybon, Laurent and Milas, Ivana}},
  issn         = {{2050-084X}},
  language     = {{eng}},
  publisher    = {{eLife Sciences Publications}},
  series       = {{eLife}},
  title        = {{Inhibition of the serine protease HtrA1 by SerpinE2 suggests an extracellular proteolytic pathway in the control of neural crest migration}},
  url          = {{http://dx.doi.org/10.7554/eLife.91864}},
  doi          = {{10.7554/eLife.91864}},
  volume       = {{12}},
  year         = {{2023}},
}