Genetic Control of Axial Patterning in Drosophila Eye

描述（由申请人提供）：在器官发生过程中，轴向模式对生长发育至关重要。果蝇为眼原基的背腹侧（DV）模式和生长提供了一个理想的遗传分析模型。DV图案是眼内形成的第一个轴。我们的目标是确定参与早期眼睛模式的关键基因。在早期眼视盘中，DV模式是通过启动背侧选择基因pannier （pnr）的表达而建立的，该基因控制无翼（wg）信号基因和易洛魁家族转录因子的表达。背侧基因可拮抗腹侧基因(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节相互作用的分子遗传学基础。在腹侧结构域，一个Notch配体Serrate （Ser）和一个新的蛋白Lobe (L)起着关键作用。L在背侧和腹侧都有表达，但作为Notch信号通路的一个组成部分，仅在眼腹侧生长中需要表达。L是腹侧眼发育、生长和存活所必需的。理解L函数的分子遗传基础的细胞生存,规范和增长,我们将使用分子遗传学方法普遍采用在果蝇模型系统的功能分析(i) L和Homothorax (Hth),负眼发展的调节器,控制眼睛增长(2)L函数在视网膜细胞命运决定和分化,和(iii)的函数L Cullin-4, E3泛素连接酶,在腹侧眼的控制细胞的生存。这些研究将有助于阐明L介导的Notch通路调控细胞存活、生长和模式的遗传通路。这里研究的大多数基因都是高度保守的，因为它们存在于包括人类在内的高等哺乳动物中，DV模式的遗传控制是哺乳动物眼睛发育过程中的一个重要事件。这项研究将有助于揭示基因相互作用与早期眼睛发育有关的机制。因此，我们的研究也将有助于了解哺乳动物眼睛发育和儿童早期视网膜疾病的病因。

DESCRIPTION (provided by applicant): During organogenesis axial patterning is essential for growth and development. The fruit fly, Drosophila, provides an ideal model for genetic analysis of dorsoventral (DV) patterning and growth of the eye primordium. DV patterning is the first axis formed in eye. Our goal is to identify key genes involved in early eye patterning. 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 that need to be addressed is the molecular genetic basis for such regulatory interactions. In the ventral domain, a Notch ligand Serrate (Ser) and a novel protein Lobe (L) play key roles. L is expressed in both dorsal and ventral domains but is only required for ventral eye growth as a component of Notch signaling pathway. L is required for ventral eye development, growth, and survival. To understand the molecular genetic basis of L functions in cell survival, specification and growth, we will use molecular genetics approaches commonly employed in Drosophila model system to analyze (i) the function of L and Homothorax (Hth), a negative regulator of eye development, in the control of eye growth (ii) the L function in retinal cell fate determination and differentiation, and (iii) function of L and Cullin-4, an E3 ubiquitin ligase, in the control of ventral eye cell survival. These studies will help to elucidate the genetic circuitry involved in L mediated Notch pathway regulation of cell survival, growth, and patterning. 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. PUBLIC HEALTH RELEVANCE: Axial patterning, a fundamental process of organogenesis in multi-cellular organisms, involves transition of a mono-layered epithelium to a three- dimensional organ. A well established model of the Drosophila melanogaster (fruit fly) will be employed to study dorso-ventral (DV) (axial) patterning and growth in the developing eye. DV patterning, the first lineage restriction event occurring in the eye, results in the formation of dorsal and ventral domains of the eye. The border between the dorsal and ventral domains of the eye is the site of Notch (N) signaling pathway which regulates cell proliferation and differentiation of the eye. We will try to understand the genetic mechanism of DV patterning and growth during early eye imaginal disc development in Drosophila. The DV boundary is established by interactions of dorsal selector genes and ventral genes. The dorsal factors include a GATA-family transcription factor Pannier (Pnr), the secreted morphogen Wingless (Wg), and Iroquois (Iro-C) family homeobox proteins. In the ventral domain, a Notch ligand Serrate (Ser) and a novel protein Lobe (L) play key roles. L is expressed in both dorsal and ventral domains but is only required for ventral eye growth as a component of Notch signaling pathway. The Drosophila eye begins from a ventral equivalent state on which dorsal fate is established. One of the important questions is how the initial ventral fate of the eye is established and maintained. Our earlier studies have demonstrated that L is required for ventral eye development, growth, and survival. To understand the molecular genetic basis of L functions in cell survival, specification and growth, we will use molecular genetics approaches commonly employed in Drosophila model system to analyze (i) the function of L and Homothorax (Hth), a negative regulator of eye development, in the control of eye growth (ii) the L function in retinal cell fate determination and differentiation, and (iii) function of L and Cullin-4, an E3 ubiquitin ligase, in the control of ventral eye cell survival. These studies will help to elucidate the genetic circuitry involved in L mediated Notch pathway regulation of cell survival, growth, and patterning. Since the genetic machinery is highly conserved it will be interesting to extrapolate the information to higher vertebrates. These studies will contribute towards understanding the genetic mechanism of early developmental events during organogenesis. The genetic machinery involved in axial patterning is highly conserved across the species. In humans and other vertebrates, DV polarity of the retina directs the retinal axon projections to the brain. These studies will shed light on the role of early developmental events that may affect the retinal axon projection to the brain. It will also help to understand the molecular basis of developmental defects caused by mutations in the human homolog of Drosophila.