Impaired αVβ8 and TGFβ 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 αVβ8 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 TGFβ signaling during a critical perinatal window, are distinct from microglia with induced reduction in TGFβ 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 αVβ8 and TGFβ signaling in coordinating microgliogenesis with brain development and implicate abnormally programmed microglia or their products in human neurodevelopmental disorders that share this neuropathology.

Lack of Flvcr2 impairs brain angiogenesis without affecting the blood-brain barrier

“…Several mouse mutants have been described as presenting brain vascular malformations during embryonic development. These mutants disrupt distinct signaling pathways, including TGF-β/integrin β8 (7,37), neuropilin-1 (38), and WNT/β-catenin (8,28). Some of these pathways may interact through unknown mechanisms to drive brain angiogenesis, since their individual mRNA levels comparable to control in our RNA-Seq from isolated brain endothelial cells.…”

αvβ8 integrin adhesion and signaling pathways in development, physiology and disease

“…Recent data suggest that defective TGFβ-regulated fatty acid metabolism in brain vascular endothelial cells contribute to the adult-onset neurological deficits (Tiwary et al, 2018). In addition, the progressive neurological deficits in mice lacking β8 integrin in the CNS have been linked to defective TGFβ receptor signaling in microglial cells (Arnold et al, 2019). Hence, the progressive neurodegeneration phenotypes in adult Itgb8-mutant mice may be due to defective TGFβ signaling in multiple cell types of the brain.…”

Microglia Development and Maturation and Its Implications for Induction of Microglia-Like Cells from Human iPSCs

“…Further studies have clearly demonstrated that TGFβ1 is essential for microglia development [ 24 ] and maturation [ 25 ]. The deletion of TGFβ1 expression in the CNS [ 17 ], impairment of extracellular TGFβ1 processing and activation [ 26 , 27 ], or silencing of microglial TGFβ1 signaling by deletion of the TGFβ1 receptor Tgfbr2 [ 28 ] resulted in a loss of microglia maturation, characterized by a lack of homeostatic microglia marker expression. Moreover, affected microglia further display an inflammatory phenotype, as evidenced by the increased expression of ApoE , Axl , Cybb , Cd74 , H2-Aa , or Il1b , further emphasizing the importance of microglial TGFβ signaling to regulate microglia reactivity [ 28 , 29 ].…”