2026
Cell Rep . 2026 Mar 24;45(3):117071. doi: 10.1016/j.celrep.2026.117071. Epub 2026 Mar 10.
Cortical astrocytic neogenin, a key protein switching HIF1/2ɑ-VEGFa-induced angiogenesis to MEGF10-driven phagocytosis
Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA. Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Department of Neurology, Fujian Medical University Union Hospital, Fuzhou, China. Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA; Beijing Tiantan Hospital, Capital Medical University, No.119, S 4(th) Ring W Rd, Fengtai District, Beijing 100070, China; Department of Neurology, Renji Hospital, Shanghai Jiao Tong University, Shanghai, China. Institute of Stroke Research, Xuzhou Medical University, Fuzhou, China. Department of Neurosciences, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
Service type: Knockout mice
Abstract
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.
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