Interplay of Zeb2a, Id2a and Batf3 regulates microglia and dendritic cell development in the zebrafish brain

In vertebrates, the central nervous system (CNS) harbours various immune cells, including parenchymal microglia, perivascular macrophages and dendritic cells, which act in coordination to establish an immune network to regulate neurogenesis and neural function, and to maintain the homeostasis of the CNS. Recent single cell transcriptomic profiling has revealed that the adult zebrafish CNS contains microglia, plasmacytoid dendritic cells (pDCs) and two conventional dendritic cells (cDCs), ccl35+ cDCs and cnn3a+cDCs. However, how these distinct myeloid cells are established in the adult zebrafish CNS remains incompletely defined. Here, we show that the Inhibitor of DNA binding 2a (Id2a) is essential for the development of pDCs and cDCs but is dispensable for the formation of microglia, whereas the Basic leucine zipper transcription factor ATF-like 3 (Batf3) acts downstream of id2a and is required exclusively for the formation of the cnn3a+ cDC subset. In contrast, the Zinc finger E-box-binding homeobox 2a (Zeb2a) promotes the expansion of microglia and inhibits the DC specification, possibly through repressing id2a expression. Our study unravels the genetic networks that govern the development of microglia and brain-associated DCs in the zebrafish CNS.