Astrocyte morphogenesis requires self-recognition

• 成果类型: Article
• 署名作者: Lee, John H.; Sergeeva, Alina P.; Ahlsen, Goran; Mannepalli, Seetha; Bahna, Fabiana; Goodman, Kerry M.; Xu, Runzhe; Khakh, Baljit S.; Weiner, Joshua A.; Shapiro, Lawrence; Honig, Barry; Zipursky, S. Lawrence
• 署名单位: University of California System; University of California Los Angeles; Columbia University; Columbia University; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of Iowa; University of Iowa; Columbia University; Columbia University
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3401
• DOI: 10.1038/s41586-025-09013-y
• 发表日期: 2025-08-07
• 关键词: gamma-protocadherins; calcium signals; alpha; specificity; expression; diversity; avoidance; IDENTITY; beta; glia

摘要

Self-recognition is a fundamental cellular process across evolution and forms the basis of neuronal self-avoidance1, 2, 3-4. Clustered protocadherin (cPcdh) proteins, which comprise a large family of isoform-specific homophilic recognition molecules, have a pivotal role in the neuronal self-avoidance that is required for mammalian brain development5, 6-7. The probabilistic expression of different cPcdh isoforms confers unique identities on neurons and forms the basis for neuronal processes to discriminate between self and non-self5,6,8. Whether this self-recognition mechanism also exists in astrocytes remains unknown. Here we report that gamma C3, a specific isoform in the Pcdh gamma family, is enriched in human and mouse astrocytes. Using genetic manipulation, we demonstrate that gamma C3 acts autonomously to regulate astrocyte morphogenesis in the mouse visual cortex. To determine whether gamma C3 proteins act by promoting recognition between processes of the same astrocyte, we generated pairs of gamma C3 chimeric proteins that are capable of heterophilic binding to each other, but incapable of homophilic binding. Co-expression of complementary heterophilic binding isoform pairs in the same gamma C3-null astrocyte restored normal morphology. By contrast, chimeric gamma C3 proteins individually expressed in single gamma C3-null mutant astrocytes did not. These data establish that self-recognition mediated by gamma C3 contributes to astrocyte development in the mammalian brain.