RESUMO
In vertebrates, the ontogeny of microglia, the resident macrophages of the central nervous system, initiates early during development from primitive macrophages. Although murine embryonic microglia then persist through life, in zebrafish these cells are transient, as they are fully replaced by an adult population originating from larval hematopoietic stem cell (HSC)-derived progenitors. Colony-stimulating factor 1 receptor (Csf1r) is a fundamental regulator of microglia ontogeny in vertebrates, including zebrafish, which possess two paralogous genes: csf1ra and csf1rb Although previous work has shown that mutation in both genes completely abrogates microglia development, the specific contribution of each paralog remains largely unknown. Here, using a fate-mapping strategy to discriminate between the two microglial waves, we uncover non-overlapping roles for csf1ra and csf1rb in hematopoiesis, and identified csf1rb as an essential regulator of adult microglia development. Notably, we demonstrate that csf1rb positively regulates HSC-derived myelopoiesis, resulting in macrophage deficiency, including microglia, in adult mutant animals. Overall, this study contributes to new insights into evolutionary aspects of Csf1r signaling and provides an unprecedented framework for the functional dissection of embryonic versus adult microglia in vivo.
Assuntos
Microglia/metabolismo , Mutação/genética , Proteínas Tirosina Quinases/genética , Proteínas de Peixe-Zebra/genética , Peixe-Zebra/genética , Envelhecimento/genética , Animais , Embrião não Mamífero/metabolismo , Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Hematopoese , Células-Tronco Hematopoéticas/metabolismo , Macrófagos/metabolismo , Células Mieloides/metabolismo , Fagócitos/metabolismo , Proteínas Tirosina Quinases/metabolismo , Receptores Proteína Tirosina Quinases/genética , Receptores Proteína Tirosina Quinases/metabolismo , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/metabolismoRESUMO
Microglia, the tissue-resident macrophages of the CNS, represent major targets for therapeutic intervention in a wide variety of neurological disorders. Efficient reprogramming protocols to generate microglia-like cells in vitro using patient-derived induced pluripotent stem cells will, however, require a precise understanding of the cellular and molecular events that instruct microglial cell fates. This remains a challenge since the developmental origin of microglia during embryogenesis is controversial. Here, using genetic tracing in zebrafish, we uncover primitive macrophages as the unique source of embryonic microglia. We also demonstrate that this initial population is transient, with primitive microglia later replaced by definitive microglia that persist throughout adulthood. The adult wave originates from cmyb-dependent hematopoietic stem cells. Collectively, our work challenges the prevailing model establishing erythro-myeloid progenitors as the sole and direct microglial precursor and provides further support for the existence of multiple waves of microglia, which originate from distinct hematopoietic precursors.