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）：在器官发生期间，轴向模式对于生长和发育至关重要。果蝇的果蝇为背腹（DV）模式和眼睛原始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。我们的目标是确定与早期构图有关的关键基因。在早期的想象盘中，通过启动背侧选择器基因Pannier（PNR）的表达来确定DV模式，该基因控制无翼（WG）信号基因和易洛魁族家族转录因子的表达。背基因拮抗腹侧基因的功能，包括叶（L），锯齿（Serrate（Serrate）（Ser）和边缘（FNG）。这两组基因的相互作用导致DV边界处的Notch信号传导的优先激活，以诱导生长和分化。需要解决的主要问题之一是这种调节相互作用的分子遗传基础。在腹侧结构域中，凹槽配体锯齿（Ser）和新型蛋白叶（L）扮演关键角色。 L在背侧和腹侧结构域中表达，但仅作为Notch信号通路的组成部分，仅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。 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泛素连接酶在控制腹眼细胞存活中。这些研究将有助于阐明与L介导的Notch途径调节细胞存活，生长和图案的遗传回路。这里研究的大多数基因都具有高度保守的，因为它们存在于包括人类在内的较高哺乳动物中，而对DV模式的遗传控制是哺乳动物眼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涉及的遗传相互作用的机制。因此，我们的研究还将有助于理解儿童早期视网膜疾病的哺乳动物眼发育和病因。 公共卫生相关性：轴向图案是多细胞生物中器官发生的基本过程，涉及将单层上皮过渡到三维器官。果蝇果蝇（果蝇）的建立良好模型将用于研究发育中的眼睛中的多索 - 腹膜（DV）（轴向）图案和生长。 DV模式是在眼中发生的第一个谱系限制事件，导致眼睛的背和腹侧结构域的形成。眼睛背侧和腹侧域之间的边界是调节细胞增殖和眼睛分化的Notch（N）信号通路的位点。我们将尝试了解果蝇早期想像盘发育期间DV模式和生长的遗传机制。 DV边界是通过背面选择器基因和腹侧基因的相互作用建立的。背侧因子包括GATA家庭转录因子Pannier（PNR），分泌的形态学无翼（WG）和iroquois（IRO-C）家族同源蛋白。在腹侧结构域中，凹槽配体锯齿（Ser）和新型蛋白叶（L）扮演关键角色。 L在背侧和腹侧结构域中表达，但仅作为Notch信号通路的组成部分，仅是腹侧眼生长所必需的。果蝇的眼睛从建立背侧命运的腹侧等效状态开始。重要的问题之一是如何确定和维护眼睛的初始腹侧命运。我们较早的研究表明，L是腹眼发育，生长和生存所必需的。 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泛素连接酶在控制腹眼细胞存活中。这些研究将有助于阐明与L介导的Notch途径调节细胞存活，生长和图案的遗传回路。由于遗传机制是高度保守的，因此将信息推断到更高的脊椎动物将很有趣。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。轴向图案中涉及的遗传机制在整个物种中都高度保守。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向大脑。这些研究将阐明可能影响视网膜轴突投射到大脑的早期发育事件的作用。它还将有助于理解由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