Molecular mechanisms underlying microglial colonization and efferocytosis in zebrafish

Abstract

Microglia are the central nervous system (CNS)-resident macrophages involved in neural inflammation, neurogenesis, and neural activity regulation. Because microglial precursors – peripheral macrophages are born in peripheral hematopoietic tissues, the establishment of microglia pool in the CNS involves two processes: colonization – homing of macrophages from peripheral tissues to the CNS; maturation – differentiation of brain-colonizing macrophages into microglia. Previous studies have shown that apoptotic neurons facilitate microglia colonization of the brain and in turn microglia extensively phagocytose these dying neurons in embryonic zebrafish. However, the molecular mechanisms underlying neuronal apoptosis-mediated microglia colonization and phagocytosis of dying neurons remain undefined. Here, we show that basic leucine zipper (b-Zip) transcription factors, Mafba and Mafbb, two zebrafish orthologues of mammalian MAFB, play a critical role in neuronal apoptosis-mediated microglia colonization in zebrafish. We document that loss of Mafba and Mafbb function perturbs microglia colonization of developing zebrafish brain. We further demonstrate that Mafba and Mafbb act cell-autonomously and co-operatively to orchestrate microglia colonization by regulating the expression of G protein-coupled receptor 34a (Gpr34a) which directs peripheral macrophage recruitment into the brain through sensing lysophosphatidylserine (lysoPS) released by apoptotic neurons. In addition, we found that Mafba and Mafbb are also essential to microglia efferocytosis. We illustrate that combined deficiency of Mafba and Mafbb disrupts microglia efferocytosis and the impairment of phagosome formation is one of the major causes of this defect. Our study reveals the critical roles of Mafba and Mafbb in the regulation of microglia colonization and efferocytosis in early embryonic zebrafish.

Date of Award	2022
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology
Supervisor	Zilong WEN (Supervisor)