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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 H, 2025. "Radial glia integrin avb8 regulates cell autonomous microglial TGFβ1 signaling that is necessary for microglial identity," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-57684-y
    DOI: 10.1038/s41467-025-57684-y
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    References listed on IDEAS

    as
    1. Lipin Loo & Jeremy M. Simon & Lei Xing & Eric S. McCoy & Jesse K. Niehaus & Jiami Guo & E. S. Anton & Mark J. Zylka, 2019. "Single-cell transcriptomic analysis of mouse neocortical development," Nature Communications, Nature, vol. 10(1), pages 1-11, December.
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