Department of Biological Sciences and Border Biomedical Research Center, University of Texas at El Paso, El Paso, TX.
Blood Adv. 2019 Apr 23;3(8):1244-1254. doi: 10.1182/bloodadvances.2018024539.
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.
红细胞生成是新的红细胞（RBC）形成的过程，该过程中的缺陷可导致贫血或地中海贫血。GATA1 转录因子是 RBC 发育的既定介质。然而，调节表达的上游机制尚未完全阐明。胆固醇是表达的 1 种潜在上游介质，因为先前的研究表明胆固醇合成缺陷会破坏 RBC 分化。在这里，我们在携带单个错义突变的斑马鱼中对 RBC 发育进行了表征（Vu57 等位基因）。编码胆固醇合成途径中的第一种酶，突变抑制胆固醇合成。我们分析了突变体及其野生型兄弟姐妹中的 RBC 数量。突变导致成熟 RBC 的数量减少，这与表达减少相符。我们将这些实验与药理学抑制相结合，并证实胆固醇和异戊二烯合成对于 RBC 分化至关重要，但表达是异戊二烯依赖性的。总的来说，我们的结果揭示了 RBC 发育的 2 种新的上游调节剂，并表明适当的胆固醇动态平衡对于原始红细胞生成至关重要。
