复旦大学Hongyan Wang等研究人员合作发现，endorepellin和neurexin的相互作用可引发神经上皮自噬并维持神经管发育。这一研究成果于2024年3月15日在线发表在国际学术期刊《科学通报》上。

研究人员表示，硫酸肝素蛋白聚糖2（HSPG2）基因编码基质蛋白Perlecan，该基因的遗传失活会导致小鼠胚胎死亡，并伴有严重的神经管缺陷（NTD）。

研究人员在369例NTD中发现了10%的HSPG2罕见基因变异，而对照组中仅有4%。众所周知，endorepellin是一种从Perlecan的V结构域切割而来的多肽，可促进血管生成和内皮细胞的自噬。迄今为止，endorepellin在神经发育中的作用仍不清楚。研究人员发现，endorepellin可以迁移到神经上皮细胞，然后在体内被识别并与神经上皮细胞受体neurexin结合。通过内吞途径，endorepellin和neurexin相互作用，在生理上引发自噬，并作为阻断剂适当调节神经干细胞向神经元的分化，这是正常神经管闭合所需的。

研究人员利用经过CRISPR/Cas9基因编辑的精子样干细胞，创建了具有人源HSPG2变体的基因敲入（KI）小鼠模型。研究人员意识到，任何影响endorepellin功能的HSPG2变体都被认为是人类NTD的致病因变体，因为与野生型胚胎相比，这些KI胚胎表现出的严重NTD表型发生的反应频率要高得多。这项研究为有效确认其他遗传疾病的致病突变提供了范例。此外，研究人员还证明，在细胞水平使用自噬抑制剂可以抑制神经元分化。因此，自噬激动剂可以防止因有害的endorepellin变体导致的自噬维持失败，和神经元过度分化而引起的NTD。

附：英文原文

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

Author: anonymous

Issue&Volume: 2024/03/15

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.

DOI: 10.1016/j.scib.2024.03.026

Source: https://www.sciencedirect.com/science/article/abs/pii/S2095927324001828