Ovarian development is a process that requires coordinated growth and differentiation of the germline (oocyte) and its surrounding somatic cells. In mammals, multicellular layers of somatic follicle cells serve to communicate directly with the oocyte, to interact with the extra-cellular matrix, and to support the physical integrity of the follicle. Epithelial integrity therefore plays an integral role in ovary development although the underlying cellular and molecular mechanisms have yet to be elucidated. Such knowledge is critical for understanding reproductive biology as well as pathology. For example, loss of epithelial adherens junctions in the ovarian surface epithelium has been implicated in the onset of invasive ovarian cancer. In Drosophila egg chambers, the multiple epithelial functions are assumed by a single layer of follicle cells. This provides a very accessible model for analyzing the follicular epithelial development and its influence on the oocyte development. In our previous studies on the EGF receptor (EGFR) signaling that specifies the follicular cell fates, we identified the Drosophila homolog of the von Hippel-Lindau tumor suppressor gene (VHL) as a modulator of EGFR signaling. More in-depth studies revealed that VHL played a much larger role in organizing the polarity and integrity of the follicular epithelium. In the VHL knock-down mutant, three distinct phenotypes are observed: 1) A typical ventralized phenotype resulting from mislocalized EGFR; 2) A short-and-fat phenotype similar to that caused by integrin mutations; and 3) A degenerated egg chamber phenotype associate with multilayering of the epithelium and breakdown of the adherens junctions. Thus, VHL is potentially a central organizing activity that coordinates the basal adhesion (integrin) and apicolateral (adherens) junctions. We have also found that the VHL protein can interact directly, both in vivo and in vitro, with the homolog of the putative human metastasis inhibitor nm23. A working model is proposed to study the formation of follicular epithelium, focusing on the functions of these two tumor-related gene function.
Four specific Aims are designed:
Aim 1 : To elucidate the functional relationship between VHL and nm23/Awd.
Aim 2 : To determine the underlying mechanism of EGFR mislocalization in DVHL mutant.
Aim 3 : To analyze the role of Rac in linking integrin and DE-cadherin functions.
Aim 4 : To isolate additional DVHL and novel Awd interacting protein. ? ?
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