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XB-ART-60672
Elife 2024 Apr 18;12. doi: 10.7554/eLife.91864.
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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 EM , Nilsson-De Moura J , Pomeshchik Y , Roybon L , Milas I .


Abstract
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.

PubMed ID: 38634469
PMC ID: PMC11026092
Article link: Elife
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: dnph1 fn1 foxd3 htra1 htra2 htra3 htra4 itk myc plg sdc4 serpine2 snai1 snai2 sox9 twist1
GO keywords: neural crest cell migration [+]
Antibodies: Actb Ab10 Tuba4a Ab3
Morpholinos: htra1 MO1 serpine2 MO1 serpine2 MO2 serpine2 MO3 serpine2 MO5

Phenotypes: Xal wt + Tg(Xla.hrta1-FLAG) (Fig. 7 CC') [+]

Article Images: [+] show captions
References [+] :
Acosta, The serpin PN1 is a feedback regulator of FGF signaling in germ layer and primary axis formation. 2015, Pubmed, Xenbase