Mutations in the zebrafishhmgcs1gene reveal a novel function for isoprenoids during red blood cell development

Abstract

AbstractErythropoiesis is the process by which new red blood cells (RBCs) are formed and defects in this process can lead to anemia or thalassemia. The GATA1 transcription factor is an established mediator of RBC development. However, the upstream mechanisms that regulate the expression ofGATA1are not completely characterized. Cholesterol is one potential upstream mediator ofGATA1expression because previously published studies suggest that defects in cholesterol synthesis disrupt RBC differentiation. Here we characterize RBC development in a zebrafish harboring a single missense mutation in thehmgcs1gene (Vu57 allele).hmgcs1encodes the first enzyme in the cholesterol synthesis pathway and mutation ofhmgcs1inhibits cholesterol synthesis. We analyzed the number of RBCs inhmgcs1mutants and their wildtype siblings. Mutation ofhmgcs1resulted in a decrease in the number of mature RBCs, which coincides with reducedgata1aexpression. We combined these experiments with pharmacological inhibition and confirmed that cholesterol and isoprenoid synthesis are essential for RBC differentiation, but thatgata1aexpression is isoprenoid dependent. Collectively, our results reveal two novel upstream regulators of RBC development and suggest that appropriate cholesterol homeostasis is critical for primitive erythropoiesis.Key PointsThe products of the cholesterol synthesis pathway regulate red blood cell development during primitive erythropoiesis.Isoprenoids regulate erythropoiesis by modulating the expression of the GATA1 transcription factor.