The interaction of endorepellin and neurexin triggers neuroepithelial autophagy and maintains neural tube development.

Autor: Lu L; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China; Obstetrics & Gynecology Hospital, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China., Bai M; Key Laboratory of Multi-Cell Systems, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China., Zheng Y; Obstetrics & Gynecology Hospital, The Institute of Obstetrics and Gynecology, Fudan University, Shanghai 200090, China., Wang X; Key Laboratory of Multi-Cell Systems, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China., Chen Z; Obstetrics & Gynecology Hospital, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China., Peng R; Obstetrics & Gynecology Hospital, The Institute of Obstetrics and Gynecology, Fudan University, Shanghai 200090, China., Finnell RH; Center for Precision Environmental Health, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston 77031, USA., Zhao T; Shanghai Key Laboratory of Metabolic Remodeling and Health, Institute of Metabolism and Integrative Biology, Fudan University, Shanghai 200438, China., Li C; Shanghai Medical College, Fudan University, Shanghai 200032, China., Wu B; Prenatal Diagnosis Center of Shenzhen Maternity & Child Healthcare Hospital, Shenzhen 518028, China., Lei Y; Center for Precision Environmental Health, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston 77031, USA. Electronic address: yunping.lei@bcm.edu., Li J; Key Laboratory of Multi-Cell Systems, Shanghai Key Laboratory of Molecular Andrology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: jsli@sibcb.ac.cn., Wang H; Obstetrics & Gynecology Hospital, State Key Laboratory of Genetic Engineering, Fudan University, Shanghai 200032, China; Prenatal Diagnosis Center of Shenzhen Maternity & Child Healthcare Hospital, Shenzhen 518028, China; Children's Hospital, Fudan University, Shanghai 201102, China. Electronic address: wanghy@fudan.edu.cn.
Jazyk: angličtina
Zdroj: Science bulletin [Sci Bull (Beijing)] 2024 Jul 30; Vol. 69 (14), pp. 2260-2272. Date of Electronic Publication: 2024 Mar 15.
DOI: 10.1016/j.scib.2024.03.026
Abstrakt: Heparan sulfate proteoglycan 2 (HSPG2) gene encodes the matrix protein Perlecan, and genetic inactivation of this gene creates mice that are embryonic lethal with severe neural tube defects (NTDs). We discovered rare genetic variants of HSPG2 in 10% cases compared to only 4% in controls among a cohort of 369 NTDs. Endorepellin, a peptide cleaved from the domain V of Perlecan, is known to promote angiogenesis and autophagy in endothelial cells. The roles of enderepellin in neurodevelopment remain unclear so far. Our study revealed that endorepellin can migrate to the neuroepithelial cells and then be recognized and bind with the neuroepithelia receptor neurexin in vivo. Through the endocytic pathway, the interaction of endorepellin and neurexin physiologically triggers autophagy and appropriately modulates the differentiation of neural stem cells into neurons as a blocker, which is necessary for normal neural tube closure. We created knock-in (KI) mouse models with human-derived HSPG2 variants, using sperm-like stem cells that had been genetically edited by CRISPR/Cas9. We realized that any HSPG2 variants that affected the function of endorepellin were considered pathogenic causal variants for human NTDs given that the severe NTD phenotypes exhibited by these KI embryos occurred in a significantly higher response frequency compared to wildtype embryos. Our study provides a paradigm for effectively confirming pathogenic mutations in other genetic diseases. Furthermore, we demonstrated that using autophagy inhibitors at a cellular level can repress neuronal differentiation. Therefore, autophagy agonists may prevent NTDs resulting from failed autophagy maintenance and neuronal over-differentiation caused by deleterious endorepellin variants.
(Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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