Disrupting microglial TGF-β signaling triggers region-specific pathology in the spinal cord

Abstract Transforming growth factor-β (TGF-β) signaling is critical for microglial maturation during development and the maintenance of microglial homeostasis in adulthood. It remains unclear whether regional susceptibilities to the loss of TGF-β signaling in microglia also exist, and the contributing factors have yet to be identified. We find that deletion of Tgfbr2 on microglia leads to microglial activation and demyelination in mouse spinal cords, primarily in the dorsal column (DC). Tgfbr2 -deficient microglia exhibit distinct transcriptomic changes, and those sorted from the DC display a more proinflammatory profile compared to those from the ventral column (VC) and grey matter (GM). Single nucleus RNA sequencing (snRNA-seq) of the spinal cord uncovers a microglial subtype that emerges exclusively following Tgfbr2 deletion (termed TGFβ signaling-suppressed microglia, TSM), exhibiting high expression of Mmp12, Gpnmb, Lgals3, Mgll, and Alcam, predominantly located in the DC. Phenotypically, disruption of microglial TGF-β signaling results in behavioral deficits that are more severe in female and older mice, whereas young male mice are less affected. Mechanistically, we reveal a significantly higher level of TGF-β1/TGFBR2 in the spinal cords of normal older mice compared to the young mice, with the DC region richer in genes of the TGF-β signaling pathway than the VC and GM regions. This indicates that older mice and the DC region require more TGFβ1 to maintain tissue homeostasis and, reciprocally, are more responsive and sensitive to the disruption of TGF-β signaling in microglia. Herein, we report a demyelinating disease with region-specificity and its susceptibility to the loss of microglial TGF-β signaling with gender and age differences. Our findings contribute valuable information to our understanding of the importance of microglia in regulating myelin health, especially during the aging process.