Transcriptomics of Tgfb signaling

Microglia diversity emerges from interactions between intrinsic genetic programs and environment-derived signals, but how these processes unfold and interact in the developing brain remains unclear. Here, we show that radial glia progenitor-expressed integrin beta 8 activates microglia-expressed TGFB1, permitting microglial development. Domain-restricted deletion of Itgb8 in these progenitors establishes complementary domains of developmentally arrested “dysmature” microglia and homeostatic microglia that persist into adulthood. In the absence of autocrine TGFB1 signaling, we find that microglia adopt a similar reactive microglial phenotype, leading to astrogliosis and neuromotor symptoms almost identical to Itgb8 mutant mice. By comparing mice with genetic deletions in critical components downstream of Itgb8, we show that non-canonical (Smad-independent) signaling partially suppresses the dysmature microglia phenotype, associated neuromotor dysfunction and expression of disease-associated genes, providing compelling evidence for the adoption of microglial develomental signaling pathways in the context of injury or disease. We inactivated key members of Tgfb signaling in microglia (with Cx3cr1Cre) or neural progenitors (with NestinCre) and collected brain or FACS-isolated microglia. Total RNA from these samples was used for RNA-Seq.