RhoGTPases in Early Eye Development

描述(由申请人提供)：本申请的长期目标是了解早期眼睛发育的机制。更具体地说，我们希望了解肌动蛋白调节的GTP酶如何影响晶状体和视网膜上皮的协调形态发生。Rho家族GTP酶是这一应用的重点，它作为分子开关调节细胞内的信号。它们有许多不同的功能，但在肌动蛋白重排的调节中起着重要作用，从而调节细胞形状、细胞迁移和细胞突起的产生。它们还可以影响细胞的存活。我们概述了它们在早期眼形态发生中的作用：(1)确定CDc42和rac1是否在级联中调节晶状体囊泡的关闭和分离；(2)确定早期缺失的CDc42、rac1或RhoA是否导致晶状体窝内陷缺陷；(3)确定视泡在晶状体窝内陷中是否起主导作用；以及(4)确定成纤维细胞生长因子信号通路是否调节rac1、CDc42或RhoA通路的活性。这一应用对人类健康具有直接意义，因为Rho家族GTP酶与包括癌症在内的多种人类疾病有关。GTP酶在癌症病因学中的作用源于它们调节细胞黏附、细胞迁移和细胞存活的能力。我们将研究的上皮内陷过程在许多方面类似于伴随侵袭性癌症发展而来的侵袭过程。因此，这个项目可能会对癌症治疗产生影响。

DESCRIPTION (provided by applicant): The long-term goal of this application is an understanding of the mechanisms of early eye development. More specifically, we wish to understand how actin-modulating GTPases influence the coordinated morphogenesis of the lens and retinal epithelium. The Rho family GTPases that are the focus of this application act as molecular switches that regulate signaling within the cell. They function in many different capacities, but have a prominent role in the regulation of actin rearrangement and consequently, the regulation of cell shape, cell migration and the generation of cellular protrusions. They can also influence cell survival. We outline 4 aims to investigate their function in early eye morphogenesis: (1) To determine whether Cdc42 and Rac1 function in a cascade to regulate lens vesicle closure and separation, (2) To determine whether early deletion of Cdc42, Rac1 or RhoA gives a defect in lens pit invagination, (3) To determine whether the optic vesicle has a dominant role in lens pit invagination, and (4) To determine whether the FGF signaling pathway modulates activity of the Rac1, Cdc42 or RhoA pathways. This application has direct significance to human health because the Rho family GTPases are implicated in a variety of human disease including cancer. The involvement of the GTPases in the etiology of cancer is derived from their ability to regulate cell adhesion, cell migration and cell survival. The process of epithelial invagination that we will study is in many ways analogous to the process of invasion that accompanies the development of aggressive cancers. For this reasop, this project may have implications for cancer therapy.