Dipk2b promotes primitive macrophage and microglial development in zebrafish

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Abstract
Divergent Protein Kinase Domain 2B (DIPK2B) is a conserved kinase-like protein of the FAM69 family that has been associated with autism spectrum disorder and X-linked intellectual disability. However, its biological function has not yet been described. We previously identified dipk2b as a marker of hemangioblasts and hemogenic endothelial populations in the chick embryo, suggesting a potential role in hematopoietic development. Here, we characterized the expression pattern of dipk2b and the effects of its loss of function during zebrafish development. In line with our observations in the chick embryo, zebrafish dipk2b is expressed in the hematopoietic regions of the developing embryo, including the lateral plate mesoderm, dorsal aorta, and caudal hematopoietic tissue. Using two independent CRISPR/Cas9 loss-of-function alleles, we show that dipk2b homozygous mutant embryos have significantly fewer primitive macrophages than wild-type controls. In addition, dipk2b mutants exhibit a persistent decrease in microglial cell numbers at larval stages, consistent with the reduced macrophage population that gives rise to microglia. Together, these findings uncover a role for Dipk2b in promoting the development of primitive macrophages and microglia from early hematopoietic progenitors. Given the emerging role of microglial dysfunction in neurodevelopmental disorders, our results suggest that DIPK2B deficiency may contribute to autism spectrum disorder and X-linked intellectual disability by impairing microglia development.