Endorepellin和neurexin互作促进神经上皮细胞自噬并维持正常神经管发育

作     者：卢磊 白梅竹 郑煜芳 王修坤 陈仲中 彭瑞 Richard H.Finnell 赵同金 李承涛 吴波 雷云平 李劲松 王红艳 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

作者机构：Shanghai Key Laboratory of Metabolic Remodeling and HealthInstitute of Metabolism and Integrative BiologyFudan UniversityShanghai 200438China Obstetrics&Gynecology HospitalState Key Laboratory of Genetic EngineeringFudan UniversityShanghai 200032China Key Laboratory of Multi-Cell SystemsShanghai Key Laboratory of Molecular AndrologyCAS Center for Excellence in Molecular Cell ScienceShanghai Institute of Biochemistry and Cell BiologyChinese Academy of SciencesShanghai 200031China Obstetrics&Gynecology HospitalThe Institute of Obstetrics and GynecologyFudan UniversityShanghai 200090China Center for Precision Environmental HealthDepartment of Molecular and Cellular BiologyBaylor College of MedicineHouston 77031USA Shanghai Medical CollegeFudan UniversityShanghai 200032China Prenatal Diagnosis Center of Shenzhen Maternity&Child Healthcare HospitalShenzhen 518028China Children’s HospitalFudan UniversityShanghai 201102China 

出 版 物：《Science Bulletin》 (科学通报（英文版）)

年 卷 期：2024年第69卷第14期

页      面：2260-2272页

核心收录：

学科分类：1002[医学-临床医学] 100204[医学-神经病学] 10[医学] 

基　　金：supported by the National Key Research and Development Program of China(2021YFC2701100) the National Natural Science Foundation of China(81930036,32293230 and 8215008) the Commission for Science and Technology of Shanghai Municipality(20JC1418500 and 20ZR1404800) Project supported by Shanghai Municipal Science and Technology Major Project 

主　　题：Neural tube defects Androgenetic haploid embryonic stem cells Basement membrane Neural stem cell Autophagy 

摘      要：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 ***,a peptide cleaved from the domain V of Perlecan,is known to promote angiogenesis and autophagy in endothelial *** roles of enderepellin in neurodevelopment remain unclear so *** study revealed that endorepellin can migrate to the neuroepithelial cells and then be recognized and bind with the neuroepithelia receptor neurexin in *** 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 *** created knock-in(KI)mouse models with human-derived HSPG2 variants,using sperm-like stem cells that had been genetically edited by CRISPR/*** 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 *** study provides a paradigm for effectively confirming pathogenic mutations in other genetic ***,we demonstrated that using autophagy inhibitors at a cellular level can repress neuronal ***,autophagy agonists may prevent NTDs resulting from failed autophagy maintenance and neuronal over-differentiation caused by deleterious endorepellin variants.