Language
English
Publication Date
7-30-2024
Journal
Science Bulletin
DOI
10.1016/j.scib.2024.03.026
PMID
38702277
Abstract
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.
Keywords
Animals, Autophagy, Mice, Heparan Sulfate Proteoglycans, Humans, Neural Tube Defects, Neural Tube, Neural Stem Cells, Neuroepithelial Cells, Female, Male, Disease Models, Animal, Androgenetic haploid embryonic stem cells, Autophagy, Basement membrane, Neural stem cell, Neural tube defects
Published Open-Access
yes
Recommended Citation
Lu, Lei; Bai, Meizhu; Zheng, Yufang; et al., "The Interaction of Endorepellin and Neurexin Triggers Neuroepithelial Autophagy and Maintains Neural Tube Development" (2024). Faculty and Staff Publications. 4866.
https://digitalcommons.library.tmc.edu/baylor_docs/4866
Included in
Health Services Research Commons, Medical Cell Biology Commons, Medical Molecular Biology Commons, Medical Specialties Commons, Microbiology Commons