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GTP酶如何影响透镜和视网膜上皮的协调形态发生。作为本申请的焦点的Rho家族GTP酶充当调节细胞内信号传导的分子开关。它们以许多不同的能力发挥作用，但在调节肌动蛋白重排中具有突出的作用，因此，调节细胞形状，细胞迁移和细胞突起的产生。它们也可以影响细胞的存活。我们概述了4个目的，以研究它们在早期眼形态发生中的功能：（1）确定Cdc 42和Rac 1是否级联调节透镜囊泡闭合和分离，（2）确定Cdc 42、Rac 1或RhoA的早期缺失是否导致透镜小凹内陷缺陷，（3）确定视囊泡是否在透镜小凹内陷中具有主导作用，以及（4）确定FGF信号传导途径是否调节Rac 1、Cdc 42或RhoA途径的活性。该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酶参与癌症的病因学源于它们调节细胞粘附、细胞迁移和细胞存活的能力。我们将要研究的上皮内陷的过程在许多方面类似于伴随侵袭性癌症发展的侵袭过程。因此，该项目可能对癌症治疗有意义。

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.