TGF signaling mediates microglial resilience to spatiotemporally restricted myelin degeneration

Microglia survey and regulate central nervous system myelination during embryonic development and adult homeostasis. However, whether microglia-myelin interactions are spatiotemporally regulated remains unexplored. By examining spinal cord white matter tracts, we found that myelin degeneration was particularly prominent in the dorsal column (DC) during normal aging. This was accompanied by molecular and functional changes in DC microglia as well as an upregulation of TGF signaling. Disrupting TGF signaling in microglia led to unchecked microglial responses and myelin loss in the DC, accompanied by neurological deficits exacerbated with aging. snRNA-seq revealed the emergence of a TGF signaling-sensitive microglial subset and a disease-associated oligodendrocyte subset, both spatially restricted to the DC. We further discovered that microglia rely on a TGF autocrine mechanism to prevent damage of myelin in the DC. These findings demonstrate that TGF signaling is indispensable for maintaining microglial resilience to myelin degeneration in the DC during the aging process. This highlights a previously unresolved checkpoint mechanism of TGF signaling with regional specificity and spatially restricted microglia-oligodendrocyte interactions.