Radial glia integrin avb8 regulates cell autonomous microglial TGFβ1 signaling that is necessary for microglial identity

Gabriel L. McKinsey (), Nicolas Santander, Xiaoming Zhang, Kilian L. Kleemann, Lauren Tran, Aditya Katewa, Kaylynn Conant, Matthew Barraza, Kian Waddell, Carlos O. Lizama, Marie La Russa, Ji Hyun Koo, Hyunji Lee, Dibyanti Mukherjee, Helena Paidassi, E. S. Anton, Kamran Atabai, Dean Sheppard, Oleg Butovsky and Thomas D. Arnold ()
Additional contact information
Gabriel L. McKinsey: Department of Pediatrics and Newborn Brain Research Institute
Nicolas Santander: Universidad de O´Higgins
Xiaoming Zhang: Tongji Hospital affiliated to Tongji University School of Medicine
Kilian L. Kleemann: Harvard Medical School
Lauren Tran: Department of Pediatrics and Newborn Brain Research Institute
Aditya Katewa: Department of Pediatrics and Newborn Brain Research Institute
Kaylynn Conant: Department of Pediatrics and Newborn Brain Research Institute
Matthew Barraza: Department of Neuroscience
Kian Waddell: Sidney Kimmel Medical College at Thomas Jefferson University
Carlos O. Lizama: Cardiovascular Research Institute
Marie La Russa: Department of Bioengineering
Ji Hyun Koo: Department of Pediatrics and Newborn Brain Research Institute
Hyunji Lee: Department of Pediatrics and Newborn Brain Research Institute
Dibyanti Mukherjee: Department of Pediatrics and Newborn Brain Research Institute
Helena Paidassi: Univ Lyon Inserm U1111 Université Claude Bernard Lyon 1 CNRS UMR5308 ENS de Lyon
E. S. Anton: University of North Carolina at Chapel Hill
Kamran Atabai: Cardiovascular Research Institute
Dean Sheppard: Cardiovascular Research Institute
Oleg Butovsky: Harvard Medical School
Thomas D. Arnold: Department of Pediatrics and Newborn Brain Research Institute

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-57684-y

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