Impaired αVß8 and TGFß 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 αVß8 from the central nervous system (Itgb8ΔCNS mice) blocks microglia in their normal stepwise development from immature precursors to mature microglia. These "dysmature" microglia appear to result from reduced TGFß signaling during a critical perinatal window, are distinct from microglia with induced reduction in TGFß 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 αVß8 and TGFß signaling in coordinating microgliogenesis with brain development and implicate abnormally programmed microglia or their products in human neurodevelopmental disorders that share this neuropathology.