Journal
JOURNAL OF NEUROSCIENCE
Volume 40, Issue 7, Pages 1453-1482Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.0993-19.2019
Keywords
adult neurogenesis; MerTK/Axl; microglia; P2Y12; phagocytosis; secretome
Categories
Funding
- Spanish Ministry of Economy and Competitiveness
- FEDERfunds [BFU2012-32089, RYC-2013-12817, BFU2015-66689]
- BBVA Foundation [IN16,_BBM_BAS_0260]
- Basque Government Department of Education [PI_2016_1_0011]
- Ikerbasque start-up funds
- Hungarian Research and Development Fund Grant [K116654]
- Hungarian Brain Research Program Grant [2017-1.2.1-NKP-2017-00002]
- National Institutes of Health [AG060748]
- University of the Basque Country EHU/UPV
- Gangoiti Foundation Fellowship
- Basque Government
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During adult hippocampal neurogenesis, most newborn cells undergo apoptosis and are rapidly phagocytosed by resident microglia to prevent the spillover of intracellular contents. Here, we propose that phagocytosis is not merely passive corpse removal but has an active role in maintaining neurogenesis. First, we found that neurogenesis was disrupted in male and female mice chronically deficient for two phagocytosis pathways: the purinergic receptor P2Y12, and the tyrosine kinases of the TAM family Mer tyrosine kinase (MerTK)/Axl. In contrast, neurogenesis was transiently increased in mice in which MerTK expression was conditionally downregulated. Next, we performed a transcriptomic analysis of the changes induced by phagocytosis in microglia in vitro and identified genes involved in metabolism, chromatin remodeling, and neurogenesis-related functions. Finally, we discovered that the secretome of phagocytic microglia limits the production of new neurons both in vivo and in vitro. Our data suggest that microglia act as a sensor of local cell death, modulating the balance between proliferation and survival in the neurogenic niche through the phagocytosis secretome, thereby supporting the long-term maintenance of adult hippocampal neurogenesis.
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