Zebrafish macrophage developmental arrest underlies depletion of microglia and reveals Csf1r-independent metaphocytes

Abstract

Macrophages derive from multiple sources of hematopoietic progenitors. Most macrophages require colony-stimulating factor 1 receptor (CSF1R), but some macrophages persist in the absence of CSF1R. Here, we analyzed <i>mpeg1</i>:GFP-expressing macrophages in <i>csf1r</i>-deficient zebrafish and report that embryonic macrophages emerge followed by their developmental arrest. In larvae, <i>mpeg1</i>+ cell numbers then increased showing two distinct types in the skin: branched, putative Langerhans cells, and amoeboid cells. In contrast, although numbers also increased in <i>csf1r</i>-mutants, exclusively amoeboid <i>mpeg1+</i> cells were present, which we showed by genetic lineage tracing to have a non-hematopoietic origin. They expressed macrophage-associated genes, but also showed decreased phagocytic gene expression and increased epithelial-associated gene expression, characteristic of metaphocytes, recently discovered ectoderm-derived cells. We further demonstrated that juvenile <i>csf1r</i>-deficient zebrafish exhibit systemic macrophage depletion. Thus, <i>csf1r</i> deficiency disrupts embryonic to adult macrophage development. Zebrafish deficient for <i>csf1r</i> are viable and permit analyzing the consequences of macrophage loss throughout life.