Radial glia promote microglial development through integrin α_Vβ₈-TGFβ1 signaling

Abstract

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 developmental signaling pathways in the context of injury or disease.

Adult microglial TGFβ1 is required for microglia homeostasis via an autocrine mechanism to maintain cognitive function in mice

“…5, no apparent sex differences are noticed, and the sex of each animal is indicated in the figures). Our results are consistent with a recent independent study investigating the origin of TGF-β1 ligands during embryonic development 36 .…”

Dynamic fibroblast-immune interactions shape wound healing after brain injury

“…10q ). ADWA11-treated mice showed an expected cross-macrophage pro-inflammatory and “dysmature” transcriptional signature, consistent with known homeostatic roles for Itgb8 -mediated TGF β autocrine signaling in microglia 40,41 ( Extended Data Fig. 10r,s ).…”

“…To conditionally delete fibroblast Tgfbr2 , we crossed Col1a2 creERT 2 mice to Tgfbr2 flox mice (both Tgfbr2-exon2 flox , MGI 2384513, 60 and Tgfbr2-exon4 flox , Jackson 012603); Additionally, we used Itgb8 TdT mice (Itgb8-IRES-TdT, generously provided by Helena Paidassi) 61 to visualize Itgb8 expression, and Itgb8 flox mice (MGI 3608910) 62 crossed to Emx1 cre mice (Jackson 005628) to delete Itgb8 from neurons and glial cells. 41,63,64 For above conditional knockout strains, controls were littermate Cre-negative or flox-heterozygous mice.…”