Colony stimulating factor 1 signaling regulates myeloid fates in zebrafish via distinct action of its receptors and ligands

Abstract

AbstractMacrophage colony-stimulating factor receptor (M-CSFR/CSF1R) signaling is crucial for the differentiation, proliferation, and survival of myeloid cells. Therapeutic targeting of the CSF1R pathway is a promising strategy in many human diseases, including neurological disorders or cancer. Zebrafish are commonly used for human disease modeling and preclinical therapeutic screening. Therefore, it is necessary to understand the proper function of cytokine signaling in zebrafish to reliably model human-related diseases. Here, we investigate the roles of zebrafish Csf1rs and their ligands - Csf1a, Csf1b and Il34, in embryonic and adult myelopoiesis. The proliferative effect of exogenous Csf1a on embryonic macrophages is connected to both receptors as it is diminished in bothcsf1raΔ5bpandcsf1rbΔ4bpmutants. There is no evident effect of Csf1b in zebrafish embryonic myelopoiesis. Further, we uncover an unknown role of Csf1rb in zebrafish granulopoiesis. Deregulation of Csf1rb signaling leads to failure in myeloid differentiation resulting in neutropenia throughout the whole lifespan. Surprisingly, Il34 signaling through Csf1rb seems to be of high importance as bothcsf1rbΔ4bpandil34Δ5bpdeficient zebrafish larvae lack granulocytes. Our single-cell RNA sequencing analysis of adult whole kidney marrow (WKM) hematopoietic cells suggests thatcsf1rbis expressed mainly by blood and myeloid progenitors and that the expression ofcsf1raandcsf1rbis non-overlapping. We point out differentially expressed genes important in hematopoietic cell differentiation and immune response in selected WKM populations. Our findings could improve the understanding of myeloid cell function and lead to the further study of CSF1R pathway deregulation in disease, mostly in cancerogenesis.Key points:csf1raandcsf1rbare indispensable for macrophage differentiation and together withcsf1aregulate embryonic macrophage fates in zebrafishcsf1rbis important for granulocyte differentiation and migration and together withil34it regulates embryonic granulocytic fates in zebrafish