title: Phagocytic activity of neuronal progenitors regulates adult neurogenesis.
abstract: Whereas thousands of new neurons are generated daily during adult life, only a fraction of them survive and become part of neural circuits; the rest die, and their corpses are presumably cleared by resident phagocytes. How the dying neurons are removed and how such clearance influences neurogenesis are not well understood. Here, we identify an unexpected phagocytic role for the doublecortin (DCX)-positive neuronal progenitor cells during adult neurogenesis. Our in vivo and ex vivo studies demonstrate that DCX(+) cells comprise a significant phagocytic population within the neurogenic zones. Intracellular engulfment protein ELMO1, which promotes Rac activation downstream of phagocytic receptors, was required for phagocytosis by DCX(+) cells. Disruption of engulfment in vivo genetically (in Elmo1-null mice) or pharmacologically (in wild-type mice) led to reduced uptake by DCX(+) cells, accumulation of apoptotic nuclei in the neurogenic niches and impaired neurogenesis. Collectively, these findings indicate a paradigm wherein DCX(+) neuronal precursors also serve as phagocytes, and that their phagocytic activity critically contributes to neurogenesis in the adult brain.
authors.affiliation: Department of Neuroscience, University of Virginia, Charlottesville, Virginia 22901, USA.
authors.forename: Zhenjie
authors.initials: Z
authors.lastname: Lu
authors.forename: Michael R
authors.initials: MR
authors.lastname: Elliott
authors.forename: Yubo
authors.initials: Y
authors.lastname: Chen
authors.forename: James T
authors.initials: JT
authors.lastname: Walsh
authors.forename: Alexander L
authors.initials: AL
authors.lastname: Klibanov
authors.forename: Kodi S
authors.initials: KS
authors.lastname: Ravichandran
authors.forename: Jonathan
authors.initials: J
authors.lastname: Kipnis
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D005260:Female; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism; D010586:Phagocytes / Q000166:cytology / Q000378:metabolism*; D010587:Phagocytosis; D013997:Time Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C000714847:Dcx protein, mouse; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; C510359:ELMO1 protein, mouse; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides