Astrocyte morphogenesis requires self-recognition

John H. Lee (), Alina P. Sergeeva, Göran Ahlsén, Seetha Mannepalli, Fabiana Bahna, Kerry M. Goodman, Runzhe Xu, Baljit S. Khakh, Joshua A. Weiner, Lawrence Shapiro, Barry Honig and S. Lawrence Zipursky ()
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John H. Lee: University of California Los Angeles
Alina P. Sergeeva: Columbia University
Göran Ahlsén: Columbia University
Seetha Mannepalli: Columbia University
Fabiana Bahna: Columbia University
Kerry M. Goodman: Columbia University
Runzhe Xu: University of California Los Angeles
Baljit S. Khakh: University of California Los Angeles
Joshua A. Weiner: The University of Iowa
Lawrence Shapiro: Columbia University
Barry Honig: Columbia University
S. Lawrence Zipursky: University of California Los Angeles

Nature, 2025, vol. 644, issue 8075, 164-172

Abstract: Abstract Self-recognition is a fundamental cellular process across evolution and forms the basis of neuronal self-avoidance1–4. 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 development5–7. 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 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.

Date: 2025
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DOI: 10.1038/s41586-025-09013-y

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