Genetic Control of Symmetry in the Eye

描述(申请人提供)：器官原基中的轴向花纹是其生长发育所必需的。果蝇为眼原基的背腹侧(DV)构型和生长的遗传分析提供了理想的模型。我们的目标是利用这个强大的遗传系统来识别与早期眼睛图案有关的关键基因，并揭示这一重要事件背后的遗传相互作用的分子机制，这标志着眼睛发育中的第一个谱系限制。 在早期的眼成像盘中，DV模式是通过启动背部选择基因pannier(PNR)的表达来建立的，该基因控制着无翼(WG)信号基因和易洛魁家族转录因子的表达。背部基因拮抗腹面基因的功能，包括叶基因(L)、锯齿基因(Ser)和条纹基因(Fng)。这两组基因的相互作用导致DV边界Notch信号的优先激活，从而诱导生长和分化。需要解决的主要问题之一是这种调控相互作用的分子遗传学基础。 根据背侧和腹侧基因之间的拮抗关系，我们认为参与DV模式形成的基因的主要功能分别是促进或抑制Pnr介导的背侧和腹侧区域的Wg信号。这些基因由参与控制细胞存活和/或细胞生长的因素进一步调节。为了验证这些假说，我们将分析(I)L和DPP在Wg信号负调控中的关系，(Ii)L和同胸在控制眼睛生长和视网膜命运中的作用，(Iii)L和cullin-4泛素连接酶在控制腹侧细胞生存中的作用，以及(Iv)FNG和Akt激酶对L在细胞生长中的调控作用。 这里研究的大多数基因都高度保守，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一项重要事件。这项研究将有助于揭示基因交互作用在眼睛早期发育中的作用机制。因此，我们的研究也将有助于理解哺乳动物的眼睛发育和儿童早期视网膜疾病的病因学。

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.