Genetic Control of Symmetry in the Eye

描述（由申请人提供）：器官原基的轴向图案对其生长和发育至关重要。果蝇为研究眼原基的背腹纹和生长提供了理想的模型。我们的目标是利用这个强大的遗传系统来确定参与早期眼模式的关键基因，并揭示这一重要事件背后的遗传相互作用的分子机制，这标志着发育中的眼的第一谱系限制。 在早期的眼成虫盘中，DV模式化是通过背选择基因pannier（pnr）的表达启动而建立的，pnr控制无翅（wg）信号基因和易洛魁族转录因子的表达。背侧基因拮抗腹侧基因Lobe（L）、Serrate（Ser）和fringe（fng）的功能。这两组基因的相互作用导致在DV边界处优先激活Notch信号传导以诱导生长和分化。要解决的主要问题之一是这样的监管相互作用的分子遗传基础。 基于背侧和腹侧基因之间的拮抗关系，我们提出参与DV图案化的基因的主要功能是分别促进或抑制背侧和腹侧域中Pnr介导的Wg信号传导。这些基因还受参与控制细胞存活和/或细胞生长的因子的调节。为了验证这些假设，我们将分析（i）L和Dpp在Wg信号负调控中的关系，（ii）L和Homothorax（Hth）在控制眼睛生长和视网膜命运决定中的功能，（iii）L和Cullin-4泛素连接酶在控制腹侧细胞存活中的功能，以及（iv）Fng和Akt激酶在细胞生长中对L功能的调节。 这里研究的大多数基因是高度保守的，因为它们存在于包括人类在内的高等哺乳动物中，DV图案的遗传控制是哺乳动物眼睛发育过程中的重要事件。这项研究将有助于揭示早期眼睛发育中的遗传相互作用机制。因此，我们的研究也将有助于了解哺乳动物的眼睛发育和儿童早期视网膜疾病的病因。

DESCRIPTION (provided by applicant): Axial patterning in organ primordium is essential for its growth and development. The fruit fly, Drosophila, provides an ideal model for genetic analysis of dorsoventral (DV) patterning and growth of the eye primordium. Our goal is to utilize this powerful genetic system to identify key genes involved in early eye patterning and reveal the molecular mechanisms of genetic interactions underlying this important event which marks first lineage restriction in developing eye. In early eye imaginal disc, the DV patterning is established by initiation of expression of a dorsal selector gene, pannier (pnr), which controls the expression of wingless (wg) signaling gene and Iroquois family transcription factors. The dorsal genes antagonize the function of ventral genes including Lobe (L), Serrate (Ser) and fringe (fng). The interaction of these two groups of genes leads to preferential activation of Notch signaling at the DV border to induce growth and differentiation. One of the major questions to be addressed is the molecular genetic basis for such regulatory interactions. Based on antagonistic relationship between the dorsal and ventral genes, we propose that the major function of genes involved in DV patterning is to either promote or suppress the Pnr-mediated Wg signaling in the dorsal and ventral domains, respectively. These genes are further regulated by factors involved in the control of cell survival and/or cell growth. To test these hypotheses, we will analyze (i) relationship between L and Dpp in the negative regulation of Wg signaling, (ii) the function of L and Homothorax (Hth) in the control of eye growth and retinal fate determination, (iii) function of L and Cullin-4 ubiquitin ligase in the control of ventral cell survival, and (iv) the regulation of L function by Fng and Akt kinase in cell growth. Most of the genes studied here are highly conserved as they are present in higher mammals including humans, and genetic control of DV patterning is an important event during mammalian eye development. This study will help in revealing mechanisms of genetic interactions involved in early eye development. Thus, our study will also contribute to the understanding of mammalian eye development and etiology of early childhood retinal diseases.