Rac1 and Rac2 Guanosine Triphosphatases in Erythroid Function and Differentiation

Rho鸟苷三磷酸酶（GTP酶）Rac 1和Rac 2调节肌动蛋白细胞骨架， 微管动力学、基因转录、增殖和多种细胞类型中的存活。他们一直 显示在肌动蛋白组织、细胞存活和增殖中具有重叠和不同的作用， 各种造血细胞谱系。然而，其在红系前体和红细胞中的作用尚未被证实。 被评估。使用基因靶向小鼠，我们发现Rac 1和Rac 2 GTP酶的缺陷， 引起红系细胞中的显著表型：轻度贫血伴相对网织红细胞增多， 溶血性（红细胞骨架结构异常，机械稳定性降低）和 红细胞生成障碍红细胞生成主要在早期阶段受到影响，此时干细胞因子 (SCF)扮演着关键的角色。因此，我们假设Rac GTP酶（1）动态调节 红细胞骨架的结构和功能，以及（2）在归巢，增殖， 红细胞前体的存活和分化，可能通过激活的交叉信号通路， SCF受体，c-Kit。为了验证我们的假设，我们提出了一个系统的表征的影响， Rac GT3缺乏对红细胞骨架中肌动蛋白聚合机制的影响， 肌动蛋白相关蛋白和评估Rac与其他Rho GTP酶的可能串扰， 信号分子同时，我们将研究Rac 1”/"; Rac 2”/”中红细胞生成的扰动。 小鼠，寻找Rac GTP酶的机制，整合来自以下一种或多种的多种信号： 红细胞生成细胞因子影响红细胞生成。这两个提议的目标旨在探索和测试如何 Rac GTP酶调节红细胞发育、形态发生和红细胞的结构-功能关系 细胞骨架及其组成部分。 中心目标是确定参与正常红细胞系的关键分子信号通路， 发育和RBC结构膜生物学。从长远来看，这项研究有望提供 对溶血性贫血发病机制的新观点，并提供潜在的治疗靶点， 以红细胞生成异常和红细胞存活率降低为特征的人类疾病。

The Rho guanosine triphosphatases (GTPases) Rac1 and Rac2 regulate actin cytoskeleton, microtubule dynamics, gene transcription, proliferation, and survival in multiple cell types. They have been shown to have overlapping as well as distinct roles in actin organization, cell survival, and proliferation in various hematopoietic cell lineages. However their role in erythroid precursors and erythrocytes has not been evaluated. Using gene-targeted mice we have found that deficiency of Rac1 and Rac2 GTPases causes a significant phenotype in erythroid lineage: mild anemia with relative reticulocytosis, both hemolytic (abnormal structure of the erythrocyte cytoskeleton with decreased mechanical stability) and dyserythropoietic in nature. Erythropoiesis is affected mainly at the early stages, when stem cell factor (SCF) plays a critical role. We therefore hypothesize that Rac GTPases (1) dynamically regulate the structure and function of the erythrocyte cytoskeleton, and (2) play a critical role in homing, proliferation, survival, and differentiation of erythroid precursors, likely intersecting signaling pathways activatedvia the SCF receptor, c-Kit. To test our hypotheses, we propose a systematic characterization of the effects of Rac GTPase deficiency on the actin polymerization mechanics in the RBC cytoskeleton, with analysis of the actin-associated proteins and evaluation of possible cross-talk of Rac with other Rho GTPases and signaling molecules. In parallel, we will investigate the perturbations of erythropoiesis in Rac1"/";Rac2"/" mice, seeking the mechanism/s by which Rac GTPases, integrating multiple signals from one or more of the erythropoietic cytokines, affect erythropoiesis. These two proposed aims intent to explore and test how Rac GTPases regulate erythroid development, morphogenesis, and structure-function relation of the RBC cytoskeleton and its components. The central goal is to define critical molecular signaling pathways that participate in normal erythroid development and RBC structural membrane biology. In the long-term, this research is expected to offer new perspectives on the pathogenesis of hemolytic anemia and provide potential therapeutic targets in human disease characterized by abnormal erythropoiesis and decreased RBC survival.