Mafba and Mafbb regulate microglial colonization of zebrafish brain via controlling chemotaxis receptor expression

作者：Lou, Liang; Yu, Tao; Dai, Yimei; Zhao, Shizheng; Feng, Shachuan; Xu, Jin; Wen, Zilong^*

来源：PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2022, 119(39): e2203273119.

DOI：10.1073/pnas.2203273119

• microglia
• colonization
• Mafb
• lysoPS
• Gpr34a

Microglia are the central nervous system (CNS)-resident macrophages involved in neu-ral inflammation, neurogenesis, and neural activity regulation. Previous studies have shown that naturally occurring neuronal apoptosis plays a critical role in regulating microglial colonization of the brain in zebrafish. However, the molecular signaling cascades underlying neuronal apoptosis-mediated microglial colonization and the regu-lation of these cascades remain undefined. Here, we show that basic leucine zipper (b-Zip) transcription factors, Mafba and Mafbb, two zebrafish orthologs of mammalian MAFB, are key regulators in neuronal apoptosis-mediated microglial colonization of the brain in zebrafish. We document that the loss of Mafba and Mafbb function per-turbs microglial colonization of the brain. We further demonstrate that Mafba and Mafbb act cell-autonomously and cooperatively to orchestrate microglial colonization, at least in part, by regulating the expression of G protein-coupled receptor 34a (Gpr34a), which directs peripheral macrophage recruitment into the brain through sensing the lysophosphatidylserine (lysoPS) released by the apoptotic neurons. Our study reveals that Mafba and Mafbb regulate neuronal apoptosis-mediated microglial colonization of the brain in zebrafish via the lysoPS-Gpr34a pathway.SignificanceMicroglia are a subpopulation of macrophages residing in the central nervous system (CNS). Because microglial precursors/ peripheral macrophages are born in peripheral hematopoietic tissues, the establishment of a microglia pool in the CNS involves two processes: colonization, the homing of macrophages from peripheral tissues to the CNS, and maturation, the differentiation of brain-colonizing macrophages into microglia. This study aims to investigate the molecular mechanisms underlying microglial colonization during early development. Utilizing a zebrafish model system, we show that Mafba and Mafbb, two zebrafish orthologs of mammalian MAFB essential for macrophage differentiation and phagocytosis, regulate microglial colonization of the brain via modulating the lysoPS-Gpr34a signaling pathway during early embryogenesis. Our findings reveal a previously unappreciated genetic mechanism involved in microglial colonization of the brain.

• 单位
  北京大学