AREA: Mechanisms Underlying EGFR Signaling Distribution in Epithelial Tissues

描述(申请人提供)：表皮生长因子受体(EGFR)信号通路是动物组织发育的高度保守的调节因子。信号的错误调控与发育缺陷和癌症等病理因素有关。人们已经对EGFR激活网络的复杂性进行了广泛的研究，但对多个EGFR组分之间的协调机制还只有部分了解。此外，指导组织间新形态形成的信号变化的机制还很少被研究。果蝇的卵巢提供了一个易于处理的遗传系统，用于研究毛囊细胞(FCS)中EGFR激活的时空差异机制，毛囊细胞是一层2D上皮层 围绕着发育中的卵母细胞的细胞。FCS主要由生殖系分泌的转化生长因子-β样配体Gurken(GRK)指导，形成蛋壳的三维形态。一种形态是有腔的结构，背脊，沿着果蝇属主要分支的许多种类的蛋壳的背侧。值得注意的是，我们发现了EGFR激活结构域、GRK蛋白分布和各种背脊形态之间的定量和定性联系。结合分子、遗传和数学建模方法，我们的目标是确定控制不同物种上皮组织中不同激活水平的EGFR的机制。我们的实验和模拟初步结果支持配基定位到卵母细胞和卵母细胞的膜，以及卵母细胞周围的空间，以支持不同的信号分布在2D胚胎干细胞。考虑到EGFR激活在动物中的保守性，我们期待发现控制EGFR激活水平的新机制，这可能成为治疗组织病理的药物开发的靶点。

DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) signaling pathway is a highly-conserved regulator of tissue development across animals. Faulty regulation of signaling is associated with developmental defects and pathologies such as cancers. The complexity of the EGFR activation network has been extensively studied; however, the coordinating mechanisms of multiple EGFR components are only partially understood. Furthermore, the mechanisms governing signaling changes that guide the formation of new morphologies across tissues have been only sparsely studied. The ovaries of Drosophila melanogaster provide a tractable genetic system to study mechanisms governing spatiotemporal differences of EGFR activation in the follicle cells (FCs), a 2D layer of epithelial cells surrounding the developing oocyte. Instructed mainly by the germline secreted TGF-beta-like ligand Gurken (GRK), the FCs form the 3D morphologies of the eggshell. One morphology is a structure with a lumen, the dorsal ridge, along the dorsal side of eggshells of numerous species from major clades of the genus Drosophila. Strikingly, we found quantitative and qualitative associations among EGFR activation domains, GRK protein distributions, and varieties of dorsal ridge morphologies. Combining molecular, genetic, and mathematical modeling approaches, we aim to determine the mechanisms governing different activation levels of EGFR in epithelial tissues across different species. Our experimental and modeling preliminary results support ligand localization to the oocyte and FCs' membranes, and the perivitelline space to underlie different signaling distributions in the 2D FCs. Considering the conserved nature of EGFR activation across animals, we expect to discover new mechanisms that control the levels of EGFR activation, which may become targets of drug development to treat tissue pathologies.