Genetic Control of Axial Patterning in Drosophila Eye

果蝇眼睛轴向模式的遗传控制

• 批准号: 7839895
• 负责人: AMIT SINGH
• 金额: $ 21.83万
• 依托单位: UNIVERSITY OF DAYTON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-05 至 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7839895
• 关键词: Address; Affect; Animals; Area; Biological Assay; Biological Models; Brain; Caspase; Cell Death; Cell Proliferation; Cell Survival; Cells; Data; Defect; Development; Differentiation and Growth; Dorsal; Down-Regulation; Drosophila eye; Drosophila genus; Drosophila melanogaster; Endocytosis; Epithelium; Etiology; Event; Exhibits; Eye; Eye Development; Family; Feedback; Genes; Genetic; Goals; Growth; Growth and Development function; Homeodomain Proteins; Homologous Gene; Human; Human Genetics; Knowledge; Ligands; Light; Lobe; Mammals; Mediating; Modeling; Molecular; Molecular Genetics; Mono-S; Mutation; Notch Signaling Pathway; Organ; Organism; Organogenesis; Outcome; Pathway interactions; Pattern; Phenotype; Play; Principal Investigator; Process; Proteins; Regulation; Retina; Retinal; Retinal Diseases; Role; Signal Pathway; Signal Transduction; Site; System; Temperature; Testing; Time; Transferase; Vertebrates; Visual Fields; base; cell fate specification; early childhood; eye primordia; genetic analysis; imaginal disc; insight; interest; loss of function; morphogens; mutant; notch protein; novel; programs; public health relevance; retinal axon; transcription factor; ubiquitin ligase; ubiquitin-protein ligase

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.

描述（由申请人提供）：在器官发生过程中，轴向模式对于生长和发育至关重要。果蝇为背腹 (DV) 模式和眼原基生长的遗传分析提供了理想的模型。 DV 图案是眼睛中形成的第一个轴。我们的目标是确定参与早期眼睛模式的关键基因。在早期眼成象盘中，DV 模式是通过背侧选择基因 pannier (pnr) 的表达启动而建立的，该基因控制 wingless (wg) 信号基因和易洛魁家族转录因子的表达。背侧基因拮抗腹侧基因的功能，包括叶（L）、锯齿（Ser）和边缘（fng）。这两组基因的相互作用导致 DV 边界处的 Notch 信号优先激活，以诱导生长和分化。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。在腹侧结构域中，Notch 配体 Serrate (Ser) 和新型蛋白质 Lobe (L) 发挥着关键作用。 L 在背侧和腹侧区域均表达，但仅作为 Notch 信号通路的组成部分是腹侧眼生长所必需的。 L 是腹眼发育、生长和生存所必需的。为了了解 L 功能在细胞存活、规格和生长中的分子遗传学基础，我们将使用果蝇模型系统中常用的分子遗传学方法来分析 (i) L 和同胸 (Hth)（眼睛发育的负调节因子）的功能，在控制眼睛生长中（ii）L 在视网膜细胞命运决定和分化中的功能，以及（iii）L 和 Cullin-4（一种 E3 泛素连接酶）在控制腹侧眼细胞存活中的功能。这些研究将有助于阐明参与 L 介导的 Notch 通路调节细胞存活、生长和模式的遗传回路。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，并且 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早期眼睛发育中涉及的遗传相互作用的机制。因此，我们的研究也将有助于了解哺乳动物眼睛发育和幼儿视网膜疾病的病因学。 公共卫生相关性：轴向模式是多细胞生物器官发生的基本过程，涉及单层上皮向三维器官的转变。成熟的果蝇模型将用于研究发育中眼睛的背腹（DV）（轴向）模式和生长。 DV 图案化是眼睛中发生的第一个谱系限制事件，导致眼睛的背侧和腹侧区域的形成。眼睛的背侧和腹侧区域之间的边界是Notch（N）信号通路的位点，该信号通路调节眼睛的细胞增殖和分化。我们将尝试了解果蝇早期眼成象盘发育过程中 DV 模式和生长的遗传机制。 DV 边界是通过背侧选择基因和腹侧基因的相互作用建立的。背侧因子包括 GATA 家族转录因子 Pannier (Pnr)、分泌的形态发生素 Wingless (Wg) 和 Iroquois (Iro-C) 家族同源框蛋白。在腹侧结构域中，Notch 配体 Serrate (Ser) 和新型蛋白质 Lobe (L) 发挥着关键作用。 L 在背侧和腹侧区域均表达，但仅作为 Notch 信号通路的组成部分是腹侧眼生长所必需的。果蝇眼睛从腹侧等效状态开始，在该状态上建立了背侧命运。重要的问题之一是眼睛的初始腹侧命运是如何建立和维持的。我们早期的研究表明，L 是腹眼发育、生长和生存所必需的。为了了解 L 功能在细胞存活、规格和生长中的分子遗传学基础，我们将使用果蝇模型系统中常用的分子遗传学方法来分析 (i) L 和同胸 (Hth)（眼睛发育的负调节因子）的功能，在控制眼睛生长中（ii）L 在视网膜细胞命运决定和分化中的功能，以及（iii）L 和 Cullin-4（一种 E3 泛素连接酶）在控制腹侧眼细胞存活中的功能。这些研究将有助于阐明参与 L 介导的 Notch 通路调节细胞存活、生长和模式的遗传回路。由于遗传机制高度保守，将这些信息外推到高等脊椎动物将会很有趣。这些研究将有助于理解器官发生过程中早期发育事件的遗传机制。参与轴向模式的遗传机制在整个物种中高度保守。在人类和其他脊椎动物中，视网膜的 DV 极性将视网膜轴突投射引导至大脑。这些研究将揭示早期发育事件的作用，这些事件可能会影响视网膜轴突向大脑的投射。它还将有助于了解果蝇人类同源物突变引起的发育缺陷的分子基础。

项目成果

Novel neuroprotective function of apical-basal polarity gene crumbs in amyloid beta 42 (aβ42) mediated neurodegeneration.

• DOI: 10.1371/journal.pone.0078717
• 发表时间: 2013
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Steffensmeier AM;Tare M;Puli OR;Modi R;Nainaparampil J;Kango-Singh M;Singh A
• 通讯作者: Singh A

Annual Drosophila Research Conference, 2012.

年度果蝇研究会议，2012。

• DOI: 10.1002/dvdy.23806
• 发表时间: 2012
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Call,GeraldB;RoyPuli,Oorvashi;James,AnnaM;Pope,ChristopherR;Kango-Singh,Madhuri;Singh,Amit
• 通讯作者: Singh,Amit

Annual Drosophila research conference, 2011.

年度果蝇研究会议，2011。

• DOI: 10.1002/dvdy.22689
• 发表时间: 2011
• 期刊: Developmental dynamics : an official publication of the American Association of Anatomists
• 作者: Call,GeraldB;Verghese,Shilpi;Puli,OorvashiRoy;Hemmerle,DawnM;Kango-Singh,Madhuri;Singh,Amit
• 通讯作者: Singh,Amit

Domain specific genetic mosaic system in the Drosophila eye.

• DOI: 10.1002/dvg.22355
• 发表时间: 2013-01
• 期刊: GENESIS
• 影响因子: 1.5
• 作者: Tare, Meghana;Puli, Oorvashi Roy;Moran, Michael T.;Kango-Singh, Madhuri;Singh, Amit
• 通讯作者: Singh, Amit

Drosophila C-terminal Src kinase regulates growth via the Hippo signaling pathway.

• DOI: 10.1016/j.ydbio.2014.10.010
• 发表时间: 2015
• 期刊: Developmental biology
• 影响因子: 2.7
• 作者: H. Kwon;Indrayani Waghmare;Shilpi Verghese;Aditi Singh;Ashutosh Kumar Singh;Madhuri Kango-Singh