Back to Search
Start Over
The interaction of endorepellin and neurexin triggers neuroepithelial autophagy and maintains neural tube development.
- Source :
-
Science bulletin [Sci Bull (Beijing)] 2024 Jul 30; Vol. 69 (14), pp. 2260-2272. Date of Electronic Publication: 2024 Mar 15. - Publication Year :
- 2024
-
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.<br /> (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Mice
Humans
Neural Tube metabolism
Neural Tube embryology
Neural Tube pathology
Neural Stem Cells metabolism
Neuroepithelial Cells metabolism
Female
Male
Disease Models, Animal
Autophagy
Heparan Sulfate Proteoglycans metabolism
Heparan Sulfate Proteoglycans genetics
Neural Tube Defects genetics
Neural Tube Defects metabolism
Neural Tube Defects pathology
Subjects
Details
- Language :
- English
- ISSN :
- 2095-9281
- Volume :
- 69
- Issue :
- 14
- Database :
- MEDLINE
- Journal :
- Science bulletin
- Publication Type :
- Academic Journal
- Accession number :
- 38702277
- Full Text :
- https://doi.org/10.1016/j.scib.2024.03.026