A zebrafish model of Granulin deficiency reveals essential roles in myeloid cell differentiation

Abstract

Granulin (GRN) is a pleiotropic protein involved in inflammation, wound healing, neurodegenerative disease, and tumorigenesis. These roles in human health have prompted research efforts to utilize Granulin in the treatment of rheumatoid arthritis, frontotemporal dementia, and to enhance wound healing. How granulin contributes to each of these diverse biological functions, however, remains largely unknown. Here, we have uncovered a new role for granulin during myeloid cell differentiation. Using a zebrafish model of granulin deficiency, we reveal that in the absence of granulin a (grna), myeloid progenitors are unable to terminally differentiate into neutrophils and macrophages during normal and emergency myelopoiesis. In addition, macrophages fail to recruit to the wound, resulting in abnormal healing. Our CUT&RUN experiments identify Pu.1, which together with Irf8 positively regulate grna expression. Importantly, we demonstrate functional conservation between the mammalian granulin and the zebrafish orthologue grna. Our findings uncover a previously unrecognized role for granulin during myeloid cell differentiation, opening a new field of study that has the potential to impact different aspects of the human health.