Impaired ?V?8 and TGF? signaling lead to microglial dysmaturation and neuromotor dysfunction.

ABSTRACT: Microglia play a pivotal role in the coordination of brain development and have emerged as a critical determinant in the progression of neurodegenerative diseases; however, the role of microglia in the onset and progression of neurodevelopmental disorders is less clear. Here we show that conditional deletion of ?V?8 from the central nervous system (Itgb8?CNS mice) blocks microglia in their normal stepwise development from immature precursors to mature microglia. These "dysmature" microglia appear to result from reduced TGF? signaling during a critical perinatal window, are distinct from microglia with induced reduction in TGF? signaling during adulthood, and directly cause a unique neurodevelopmental syndrome characterized by oligodendrocyte maturational arrest, interneuron loss, and spastic neuromotor dysfunction. Consistent with this, early (but not late) microglia depletion completely reverses this phenotype. Together, these data identify novel roles for ?V?8 and TGF? signaling in coordinating microgliogenesis with brain development and implicate abnormally programmed microglia or their products in human neurodevelopmental disorders that share this neuropathology.

SUBMITTER: Arnold TD 

PROVIDER: S-EPMC6446869 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature