Jedi‐1/MEGF12‐mediated phagocytosis controls the pro‐neurogenic properties of microglia in the ventricular‐subventricular zone

Background The act of engulfing cellular debris profoundly shapes phagocyte phenotypes and, thus, determines tissue‐specific phagocyte function. A population of microglia with unique characteristics resides in the ventricular‐subventricular zone (V‐SVZ) neurogenic niche in neonatal mice. It is unclear whether these microglia perform phagocytosis and to what extent their phagocytic activity would support neurogenesis. We asked whether V‐SVZ‐resident microglia phagocytose apoptotic neurons and investigated whether the novel receptor Jedi‐1 mediates this process. Method Whole brain tissue or micro‐dissected V‐SVZ was collected from wild‐type and Jedi‐1 knockout (JKO) pups at postnatal day 7 (P7) and processed for immunofluorescent labeling, cytokine analysis, LC‐MS analysis of lipid mediators, microglia‐enriched culture and engulfment assays, or bulk RNA sequencing. Proliferating cells were labeled during a one‐hour pulse of EdU, delivered to the pups subcutaneously at P7. Microglia‐specific deletion of Jedi‐1 was induced with Tamoxifen, administered to the lactating dam twice daily from P1‐P3. In vivo rescue was performed via intracerebral injection of interleukin‐1 receptor antagonist at P4, followed by tissue collection at P7 for downstream analysis. Result We show that V‐SVZ microglia express Jedi‐1 and that Jedi‐1 is necessary for microglial phagocytosis both in vitro and in vivo. Furthermore, we show that loss of Jedi‐1 transforms microglial identity, leading to a neuroinflammatory phenotype consistent with that observed in neurodegenerative diseases and the aging brain. We demonstrate that loss of Jedi‐1 reduces the proliferation and neuronal differentiation of neural precursor cells in the V‐SVZ and that this effect is due to the loss of Jedi‐1 specifically in microglia. Finally, we provide evidence that the neurogenesis deficit is due to elevated interleukin‐1β levels and that in vivo inhibition of IL‐1 signaling rescues neurogenesis in the Jedi‐1 knockout V‐SVZ. Conclusion The discovery that Jedi‐1 activation engenders pro‐neurogenic microglia reveals previously unknown aspects of postnatal neurogenesis and microglial function. It also provides a platform for future research on pathways that dictate microglial phenotypic changes at all life stages, both in health and in disease. Finally, these findings may provide opportunities to explore neuroprotective/neuroregenerative microglial‐targeted therapies.