Cortical astrocytic neogenin, a key protein switching HIF1/2?-VEGFa-induced angiogenesis to MEGF10-driven phagocytosis
Astrocytes play key roles in multi-cellular processes in the brain, including maintaining homeostasis of blood vessels (BVs) and clearance of damaged cell debris. The detailed underlying mechanisms remain elusive. Here, we provide evidence that cortical astrocytic neogenin (NEO1) coordinates MEGF10-mediated phagocytosis with HIF1/2? driven VEGFa-induced angiogenesis. Knocking-out (KO) NEO1 in astrocytes increases in HIF1/2?, VEGFa, and immature BVs, but decreases in MEGF10 and MEGF10-regulated phagocytosis, in mouse cortex, but not hippocampus. Further studies suggest that the NEO1-KO impairs prolyl hydroxylase domain protein (PHD) mediated HIF1/2? hydroxylation by inducing iron deficiency, thus increasing HIF1/2?-HIF1b-P300 protein complex driven VEGFa expression at the expense of HIF1ß-P300 binding to the MEGF10 promoter; consequently, reducing MEGF10 expression. Thus, these results suggest that cortical astrocytic NEO1 promotes MEGF10 mediated phagocytosis, likely by suppressing HIF1/2?-HIF1ß-P300 induced VEGFa. Overall design: RNA-seq profiling of cultured cortical astrocytes from GFAP-Cre::NEOf/f and its littermate control pups