The vertebral central nervous system (CNS) possesses a diverse set of immune cell compartments, consisting of parenchymal microglia, border-associated macrophages and dendritic cells (DCs), all of which contribute to the CNS immune defence and homeostasis. Microglia, or the tissue-resident macrophages of the CNS, function as the major immune sentinels in the zebrafish brain. A recent study has demonstrated that microglial lifespan is regulated by interleukin 34-colony stimulating factor 1 receptor a (il34-csf1ra) pathway. Furthermore, evidence has emerged from single-cell transcriptomics to show that, apart from microglia, the zebrafish CNS is inhabited by at least three distinct subsets of DCs: plasmacytoid DCs (pDCs), cnn3a⁺ conventional DCs (cDCs) and ccl35⁺ cDCs. However, little is...[ Read more ]

The vertebral central nervous system (CNS) possesses a diverse set of immune cell compartments, consisting of parenchymal microglia, border-associated macrophages and dendritic cells (DCs), all of which contribute to the CNS immune defence and homeostasis. Microglia, or the tissue-resident macrophages of the CNS, function as the major immune sentinels in the zebrafish brain. A recent study has demonstrated that microglial lifespan is regulated by interleukin 34-colony stimulating factor 1 receptor a (il34-csf1ra) pathway. Furthermore, evidence has emerged from single-cell transcriptomics to show that, apart from microglia, the zebrafish CNS is inhabited by at least three distinct subsets of DCs: plasmacytoid DCs (pDCs), cnn3a⁺ conventional DCs (cDCs) and ccl35⁺ cDCs. However, little is known about how these cells develop to seed the zebrafish brain. Our work has identified inhibitor of DNA binding 2a (id2a) as an indispensable regulator for the development of all brain-associated DCs in zebrafish. We also show that basic leucine zipper transcription factor ATF-like 3 (batf3) acts downstream of id2a and is critical for the formation of cnn3a⁺ cDCs. Zinc finger E-box-binding homeodomain 2a (zeb2a), on the other hand, suppresses the specification of DCs, while driving the proliferation of microglia, possibly by inhibiting id2a. Additionally, our study demonstrates that id2a also functions as a negative regulator of the lifespan of zebrafish microglia, including both primitive and definitive microglia. In the absence of id2a, microglia upregulate the expression of csf1ra and persist much longer in the CNS. Our study reveals an intricate network of regulators that modulates the development and longevity of the various types of immune cells in the zebrafish CNS.