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

Laura E Kuil,Valerie Wittamer,Nynke Oosterhof,Herma C Van Der Linde,Jordy Dekker,Giuliano Ferrero,Gerben Schaaf,Tereza Mikulášová,Tjakko J Van Ham,Emma De Pater,Paulina Mh Van Strien,Erik Mj Bindels,Mireia Rovira,Martina Hason

doi:10.7554/elife.53403

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 mpeg1:GFP-expressing macrophages in csf1r-deficient zebrafish and report that embryonic macrophages emerge followed by their developmental arrest. In larvae, mpeg1+ 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 csf1r-mutants, exclusively amoeboid mpeg1+ 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 csf1r-deficient zebrafish exhibit systemic macrophage depletion. Thus, csf1r deficiency disrupts embryonic to adult macrophage development. Zebrafish deficient for csf1r are viable and permit analyzing the consequences of macrophage loss throughout life.

Highlights

Tissue resident macrophages (TRMs) are phagocytic immune cells that contribute to organogenesis and tissue homeostasis
Zebrafish primitive macrophages are born in the rostral blood island on the yolk and can be detected by mpeg1:GFP expression from 22 hr post fertilization as they migrate on the yolk ball—
In csf1rDM embryos, even though primitive macrophage numbers were slightly lower at 24 hpf (~5 mpeg1+ cells), macrophage numbers did not significantly differ from controls at 42 hpf (~46 mpeg1 + cells) (Figure 1A)

Summary

Introduction

Tissue resident macrophages (TRMs) are phagocytic immune cells that contribute to organogenesis and tissue homeostasis. Perturbations in TRM production or activity can have detrimental consequences ranging from abnormal organ development to neurodegeneration and cancer (Cassetta and Pollard, 2018; Mass et al, 2017; Yang et al, 2018; Zarif et al, 2014). In vertebrates, including mammals, birds, and fishes, TRMs derive from successive waves of hematopoiesis that initiate early during development reviewed in: McGrath et al (2015). The initial two embryonic waves give rise to primitive macrophages, born in the embryonic yolk sac in mammals and birds or the rostral blood island (RBI) in fishes, and erythro-myeloid precursors (EMPs), which originate in the yolk sac and expand in the fetal liver of mammals or emerge from the posterior blood island (PBI) of fishes.

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