Radial glia integrin avb8 regulates cell autonomous microglial TGFβ1 signaling that is necessary for microglial identity
Microglial diversity arises from the interplay between inherent genetic programs and external environmental signals. However, the mechanisms by which these processes develop and interact within the growing brain are not yet fully understood. Here, we show that radial glia-expressed integrin beta 8 (ITGB8) activates microglia-expressed TGFβ1 to drive microglial development. Domain-restricted deletion of Itgb8 in these progenitors results in regionally restricted and developmentally arrested microglia that persist into adulthood. In the absence of autocrine TGFβ1 signaling, microglia adopt a similar phenotype, leading to neuromotor symptoms almost identical to Itgb8 mutant mice. In contrast, microglia lacking the canonical TGFβ signal transducers Smad2 and Smad3 have a less polarized dysmature phenotype and correspondingly less severe neuromotor dysfunction. Our study describes the spatio-temporal regulation of TGFβ activation and signaling in the brain necessary to promote microglial development, and provides evidence for the adoption of microglial developmental signaling pathways in brain injury or disease.
Authors
- Dean Sheppard (ORCID: https://orcid.org/0000-0002-6277-2036)
- Oleg Butovsky (ORCID: https://orcid.org/0000-0003-0186-8867)
- Matthew Barraza (ORCID: https://orcid.org/0000-0002-6937-6757)
- Carlos O. Lizama (ORCID: https://orcid.org/0000-0002-0471-8525)
- Hyeonji Lee (ORCID: https://orcid.org/0000-0002-1673-1452)
- Thomas D. Arnold (ORCID: https://orcid.org/0000-0002-7310-5597)
- Kamran Atabai (ORCID: https://orcid.org/0000-0001-8170-7881)
- Jasun Koo
- Kaylynn Conant (ORCID: https://orcid.org/0000-0002-8114-4318)
- Aditya Katewa (ORCID: https://orcid.org/0000-0002-8558-4329)
- Helena Païdassi (ORCID: https://orcid.org/0000-0001-9915-4365)
- Marie La Russa (ORCID: https://orcid.org/0000-0002-1758-313X)
- Kilian Kleemann (ORCID: https://orcid.org/0000-0002-2753-6804)
- Gabriel L. McKinsey (ORCID: https://orcid.org/0000-0002-5503-2830)
- Nicolás Santander (ORCID: https://orcid.org/0000-0001-8919-833X)
- Xiaoming Zhang
- Lauren T Tran
- Dibyanti Mukherjee (ORCID: https://orcid.org/0000-0001-7980-6741)
- E.S. Anton
- Kian Waddell
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Northwestern University (US)
- École Normale Supérieure de Lyon (FR)
- University of North Carolina at Chapel Hill (US)
- Tongji University (CN)
- Brigham and Women's Hospital (US)
- Centre National de la Recherche Scientifique (FR)
- Harvard University (US)
- Thomas Jefferson University (US)
- Inserm (FR)
- University of California, San Francisco (US)
- University of O'Higgins (CL)
- Global Brain Health Institute (US)
- University of North Carolina System (US)
- Tongji Hospital (CN)
- Centre International de Recherche en Infectiologie (FR)
- Philadelphia University (US)
- Stanford University (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-03-22
- DOI
- https://doi.org/10.1038/s41467-025-57684-y
- Citations
- 13
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 10.95
Funders
- Agence Nationale de la Recherche
- National Natural Science Foundation of China
- National Institutes of Health
- University of California, San Francisco
- National Eye Institute