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

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

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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 interac-tion 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 con-firming pathogenic mutations in other genetic diseases.Furthermore,we demonstrated that using autop-hagy 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.

Neural tube defectsAndrogenetic haploid embryonic stem cellsBasement membraneNeural stem cellAutophagy

Lei Lu、Meizhu Bai、Yufang Zheng、Xiukun Wang、Zhongzhong Chen、Rui Peng、Richard H.Finnell、Tongjin Zhao、Chengtao Li、Bo Wu、Yunping Lei、Jinsong Li、Hongyan Wang

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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

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

Obstetrics & Gynecology Hospital,The Institute of Obstetrics and Gynecology,Fudan University,Shanghai 200090,China

Center for Precision Environmental Health,Department of Molecular and Cellular Biology,Baylor College of Medicine,Houston 77031,USA

Shanghai Medical College,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

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National Key Research and Development Program of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaNational Natural Science Foundation of ChinaCommission for Science and Technology of Shanghai MunicipalityCommission for Science and Technology of Shanghai MunicipalityProject supported by Shanghai Municipal Science and Technology Major Project

2021YFC27011008193003632293230821500820JC141850020ZR1404800

2024

10.1016/j.scib.2024.03.026

科学通报(英文版)
中国科学院

科学通报(英文版)

CSTPCD
ISSN：1001-6538
年,卷(期)：2024.69(14)
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