Lee John H, Sergeeva Alina P, Ahlsén Göran, Mannepalli Seetha, Bahna Fabiana, Goodman Kerry M, Xu Runzhe, Khakh Baljit S, Weiner Joshua A, Shapiro Lawrence, Honig Barry, Zipursky S Lawrence
Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA, USA.
Department of Systems Biology, Columbia University, New York, NY, USA.
Nature. 2025 May 28. doi: 10.1038/s41586-025-09013-y.
Self-recognition is a fundamental cellular process across evolution and forms the basis of neuronal self-avoidance. 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 development. 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-self. Whether this self-recognition mechanism also exists in astrocytes remains unknown. Here we report that γC3, a specific isoform in the Pcdhγ family, is enriched in human and mouse astrocytes. Using genetic manipulation, we demonstrate that γC3 acts autonomously to regulate astrocyte morphogenesis in the mouse visual cortex. To determine whether γC3 proteins act by promoting recognition between processes of the same astrocyte, we generated pairs of γC3 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 γC3-null astrocyte restored normal morphology. By contrast, chimeric γC3 proteins individually expressed in single γC3-null mutant astrocytes did not. These data establish that self-recognition mediated by γC3 contributes to astrocyte development in the mammalian brain.
自我识别是一种贯穿进化过程的基本细胞过程，是神经元自我回避的基础。成簇原钙黏蛋白（cPcdh）由一大类亚型特异性同源识别分子组成，在哺乳动物大脑发育所需的神经元自我回避中起关键作用。不同cPcdh亚型的概率性表达赋予神经元独特的身份，并为神经元过程区分自我和非自我奠定基础。这种自我识别机制是否也存在于星形胶质细胞中尚不清楚。在此，我们报告Pcdhγ家族中的一种特定亚型γC3在人和小鼠星形胶质细胞中富集。通过基因操作，我们证明γC3自主作用于调节小鼠视觉皮层中星形胶质细胞的形态发生。为了确定γC3蛋白是否通过促进同一星形胶质细胞突起之间的识别发挥作用，我们构建了成对的γC3嵌合蛋白，它们能够相互异嗜性结合，但不能同源性结合。在同一个γC3基因敲除的星形胶质细胞中共表达互补的异嗜性结合亚型对可恢复正常形态。相比之下，在单个γC3基因敲除突变星形胶质细胞中单独表达的嵌合γC3蛋白则不能。这些数据表明，由γC3介导的自我识别有助于哺乳动物大脑中星形胶质细胞的发育。
