Journal article
Astrocyte morphogenesis requires self-recognition
Nature (London), Vol.644(8075), pp.164-172
08/07/2025
DOI: 10.1038/s41586-025-09013-y
PMCID: PMC12862983
PMID: 40437095
Abstract
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.
Details
- Title: Subtitle
- Astrocyte morphogenesis requires self-recognition
- Creators
- John H Lee - Neurobehavioral SystemsAlina P Sergeeva - Columbia UniversityGöran Ahlsén - Columbia UniversitySeetha Mannepalli - Columbia UniversityFabiana Bahna - Columbia UniversityKerry M Goodman - Columbia UniversityRunzhe Xu - University of California, Los AngelesBaljit S Khakh - University of California, Los AngelesJoshua A Weiner - University of IowaLawrence Shapiro - Columbia UniversityBarry Honig - Columbia UniversityS Lawrence Zipursky - University of California, Los Angeles
- Resource Type
- Journal article
- Publication Details
- Nature (London), Vol.644(8075), pp.164-172
- DOI
- 10.1038/s41586-025-09013-y
- PMID
- 40437095
- PMCID
- PMC12862983
- NLM abbreviation
- Nature
- ISSN
- 1476-4687
- eISSN
- 1476-4687
- Publisher
- Springer Nature
- Grant note
- W. M. Keck FoundationT32 Neurobehavioral Genetics: T32NS048004 NSF: IOS-2321481, NS111583
The authors would like to thank L. Tang, J. Trachtenberg, P. Katsamba and members of the Khakh and Zipursky laboratories for critical feedback; and S. Phillips for providing statistical analysis and consultation for our study. This work was supported by a grant from the W. M. Keck Foundation to S.L.Z., T32 Neurobehavioral Genetics (T32NS048004) training grant (J.H.L.) and NSF grant IOS-2321481 (B.H.). B.S.K. is supported by NS111583.
- Language
- English
- Electronic publication date
- 05/28/2025
- Date published
- 08/07/2025
- Academic Unit
- Liberal Arts and Science Admin; Psychiatry; Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984825530502771
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