Loss of Jedi-1 impairs microglia phagocytosis, resulting in reduced postnatal neurogenesis in the ventricular-subventricular zone.

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Project Summary Jedi-1 is an engulfment receptor that mediates phagocytic clearance of apoptotic sensory neurons by satellite glia in the developing murine peripheral nervous system. The clearance of apoptotic debris is also critical for the development and maintenance of the central nervous system (CNS), in particular for postnatal neurogenesis. Neurogenesis relies on the coupling of neural stem/progenitor cell (NSPC) proliferation, newborn neuron apoptosis, and clearance of the apoptotic debris. Critically, loss of phagocytosis hinders neurogenesis. Using immunofluorescent labeling in brain sections from male and female wildtype (WT) and Jedi-1 knockout mice (JKO) in the first week of postnatal life, we show that Jedi-1 is expressed in WT microglia residing in the postnatal neurogenic niche, the ventricular-subventricular zone (V-SVZ), but absent in the knockout. Therefore, we asked whether Jedi-1 expression in microglia contributes to this coupling and thereby regulates neurogenesis. To test whether loss of Jedi-1 hinders microglial phagocytic ability, we employed an in vitro engulfment assay and found that JKO microglia display a significant reduction in engulfment relative to WT microglia. This finding was recapitulated by an accumulation of apoptotic cells in the JKO V-SVZ, as shown by TUNEL assay. To determine whether loss of Jedi-1 and subsequent disruption of microglial phagocytic ability impacts neural precursor proliferation, we performed an EdU pulse at postnatal day 7 in vivo. Our findings demonstrate that JKO mice have fewer proliferating neural progenitors in the V-SVZ relative to WT mice. Furthermore, JKO mice have reduced numbers of MASH1+ newborn neurons when compared to those of WT mice. Together, these data support the hypothesis that postnatal neurogenesis is maintained in part by Jedi-1-dependent microglial phagocytosis of apoptotic cells in the V-SVZ.