Mutations in the zebrafish gene reveal a novel function for isoprenoids during red blood cell development.

Erythropoiesis 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 of are not completely characterized. Cholesterol is 1 potential upstream mediator of expression 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 the gene (Vu57 allele). encodes the first enzyme in the cholesterol synthesis pathway and mutation of inhibits cholesterol synthesis. We analyzed the number of RBCs in mutants and their wild-type siblings. Mutation of resulted in a decrease in the number of mature RBCs, which coincides with reduced expression. We combined these experiments with pharmacological inhibition and confirmed that cholesterol and isoprenoid synthesis are essential for RBC differentiation, but that a expression is isoprenoid dependent. Collectively, our results reveal 2 novel upstream regulators of RBC development and suggest that appropriate cholesterol homeostasis is critical for primitive erythropoiesis.