Cortical astrocytic neogenin, a key protein switching HIF1/2ɑ-VEGFa-induced angiogenesis to MEGF10-driven phagocytosis

Astrocytes coordinate vascular homeostasis and tissue clearance in the brain, yet how these functions are mechanistically integrated remains unclear. Here, we identify neogenin (NEO1) as a cortex-specific astrocytic regulator that links angiogenesis with phagocytosis. Astrocyte-specific deletion of NEO1 in the mouse cortex, but not the hippocampus, leads to elevated HIF1/2α levels, increased expression of the angiogenic factor VEGFa, and reduced expression of the phagocytic receptor MEGF10. Mechanistically, loss of NEO1 induces intracellular iron deficiency, resulting in impaired prolyl hydroxylase-dependent degradation of HIF1/2α. This iron dysregulation is associated with reduced hepcidin expression and increased levels of the iron exporter ferroportin. Stabilized HIF1/2α preferentially engages HIF1β-p300 complexes at the VEGFa promoter to promote angiogenesis while reducing HIF1β-p300 occupancy at the MEGF10 promoter, thereby suppressing phagocytic gene expression. Together, these findings establish NEO1 as a critical cortical astrocytic regulator that balances vascular remodeling and phagocytic capacity through control of iron homeostasis and HIF-dependent transcription.