Development and function of myeloid cells in zebrafish

Abstract

Myelopoiesis is such a complex program that gives rise to a diverse group of cells including macrophages and granulocytes. Despite the important roles that myeloid cells play in the organism, the developmental origin, genetic programs and the functions of myeloid cells still remain elusive. In our lab, by using zebrafish as model system, we developed a high temporal-spatial resolution fate mapping method by combining the Cre-ER system with the infrared laser-evoked gene operator (IR-LEGO) system. Using this method, we challenge previous view by showing that in zebrafish embryonic/larval and adult microglia arise from distinct sources. The embryonic/larval microglia are derived from the rostral blood island (RBI), a hematopoietic tissue equivalent to mouse YS for myelopoiesis, whereas the adult microglia arise from the ventral wall of dorsal aorta (VDA), the zebrafish counterpart of mouse aorta-gonads-mesonephros (AGM). We also show that the RBI- and VDA-derived microglia are developmentally regulated differently and likely perform non-redundant functions. Our study establishes a new paradigm for investigating the development and function of distinct microglia populations. To further understand the molecular mechanisms underlying myeloid development, a forward genetic screening was carried out and two mutants, mid^600-/- and myd^1120-/- were studied. In the mid^600-/- mutant, microglia were present but morphologically abnormal, functionally defective during post-phagocytosis. The gene positional cloning approach identified the mutated gene as trpml1, a non-specific cation channel causing the neurodegenerative lysosomal storage disorder called Mucolipidosis type IV in human. In the mutant fish, microglia defect correlated with excessive spontaneous neuronal activities, suggesting perhaps microglia are the key cell type responsible for the neurodegenerative disease. In addition, via analysis of the cebpα gene defective myd^1120-/- mutant, it indicated that cebpα takes essential roles in primitive myeloid progenitor maintenance. Furthermore, using candidate gene approach along with previous research data that Runx1 is a key embryonic myeloid fate regulator favoring neutrophils versus macrophages, the compound mutant of cebpα and runx1 was generated. The results implied that cebpα cooperates with runx1 and synergically regulates granulocyte development.

Date of Award	2015
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology