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Insights into the molecular mechanisms regulating microglia cell fate in vivo using the zebrafish model

par Miserocchi, Magali
Président du jury Schiffmann, Serge N.
Promoteur Wittamer, Valérie
Publication Non publié, 2023-11-29

Thèse de doctorat

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Résumé :

Microglia represent a population of resident macrophages in the central nervous system (CNS) involved in brain development and maintenance of homeostasis. As immune cells, microglial cells are the first line of defense against lesions and pathogens, contributing to tissue repair processes. Moreover, due to their direct involvement in numerous neuropathologies, microglia represent a major target for the development of new therapeutic approaches. In recent years, studies have considerably expanded our knowledge of microglia ontogeny, leading to the current model in which the microglial population, derived from early hematopoietic progenitors, is maintained locally by self-renewal. However, the molecular mechanisms underlying the differentiation, the self-renewal, and the maturation of microglial cells are still poorly understood. A precise understanding of how microglia development is regulated represents a major challenge in the field as it will help to improve reprogramming protocols for the generation of microglial cells in vitro for clinical purposes. In this work, our goal is to provide new insights into the molecular determinants underlying microglia ontogeny by taking advantage of the strengths of the zebrafish, an established model for the study of developmental hematopoiesis. We focused on two signaling pathways: Colony-stimulating factor 1 receptor (csf1r) and transforming growth factor b receptor (tgfbr), both previously identified as key regulators of microglia biology in vertebrates. As zebrafish possess two paralogous genes for CSF-1R, namely csf1ra and csf1rb, we have investigated their specific contribution to microglia ontogeny, which occurs in two successive waves in the zebrafish model. By combining the use of hematopoietic mutants for csf1ra and csf1rb with a transgenic approach, we have identified distinct functions for each paralog. According to our model, Csf1ra signaling is required for the establishment of primitive macrophage-derived embryonic microglia, whereas Csf1rb controls the ontogeny of definitive macrophages, including adult microglia. Overall, our work demonstrates that csf1ra and csf1rb are jointly required to fulfil the roles of mammalian CSF1R in myelopoiesis and provides evidence that subfunctionalization, a process where the two gene copies partition the ancestral function, contributed to the evolution of this gene family in zebrafish.In the second part of this work, we provide evidence that transforming growth factor β receptor (TGF-β) signaling acts as an essential positive regulator of microglia ontogeny in the zebrafish embryo, consistent with its established microglial maturation functions in the mouse model. This work provides a new level of precision on how TGF-β signaling mediates microglia cell fate in vivo.