Genetic Basis of Patterning and Growth in Drosophila Eye

果蝇眼睛图案和生长的遗传基础

基本信息

批准号：
9377402
负责人：
AMIT SINGH
金额：
$ 43.95万
依托单位：
UNIVERSITY OF DAYTON
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9377402
关键词：
Active Learning Binding Binding Sites Biological Process Brain Cell Differentiation process Cell Lineage Cell Proliferation Cells Chromatin Code Collection Complex Congenital Abnormality Defect Development Differentiation and Growth Dimensions Disease Distal Dorsal Drosophila eye Drosophila genus Drosophila melanogaster Ectopic Expression Enhancers Epithelium Etiology Event Eye Eye Development Family Generations Genes Genetic Genetic Epistasis Genetic Transcription Genetic study Goals Growth Head Health Homeodomain Proteins Homologous Gene Human Knowledge Lead Light Malignant Neoplasms Modeling Molecular Molecular Genetics Mono-S Mutation Neoplasm Metastasis Organ Organism Organogenesis Orthologous Gene Pathway interactions Pattern Phenotype Phosphotransferases Play Primordium Process Protein Family Proventriculus Regulation Regulator Genes Regulatory Pathway Research Retina Retinal Retinal Defect Retinal Diseases Role Signal Pathway Signal Transduction Site Testing Transcription Coactivator Transgenic Organisms Up-Regulation Vertebrates Vision Visual system structure design early childhood experimental study fly gene conservation insight loss of function monolayer morphogens notch protein paracrine retinal axon spatiotemporal three dimensional structure transcription factor undergraduate student

项目摘要

In multi-cellular organisms, axial patterning is required for transition of a mono-layered epithelium of an organ primordium to a three-dimensional organ by delineation of antero-posterior (AP), dorso-ventral (DV), and proximo-distal (PD) axis. We employ Drosophila melanogaster (fruit fly) eye model to study the highly conserved fundamental process of (axial) DV patterning and growth. During eye development, DV patterning precedes AP and PD axis patterning, and forms dorsal and ventral compartments. The border between the dorsal and the ventral domains of eye, termed equator, is the site for upregulation of the Notch (N) signaling, which regulates cell proliferation and differentiation. Discerning the mechanism of axes determination (DV) is crucial for our understanding of organogenesis as the problems with DV delineation results in developmental/ birth defects in flies to humans. Our long term goal is to understand the genetic basis of DV patterning which is established by interactions of the dorsal selector genes and the ventral genes. The Drosophila eye begins from a ventral equivalent state on which the dorsal fate is established by onset of expression of GATA-family transcription factor Pannier (Pnr), the secreted morphogen Wingless (Wg), and Iroquois (Iro-C) family proteins. In the dorsal eye, pnr is not the sole regulator of Wg expression. It strongly suggests that there may be other dorsal eye genes that are yet to be identified. To understand the molecular genetic basis of DV patterning, we will analyze the (1) Determine the role of new dorsal eye gene dve during eye development, (2) Investigate genetic hierarchy of dorsal eye patterning genes, and (3) Whether DV patterning and Hippo signaling may co-regulate Wg during DV patterning.. Given that the genetic machinery is conserved, we will also test the role of SATB1, a human ortholog of dve in the eye, which is known to be involved in growth regulation, cancer and metastasis. These studies will help discern (a) a new role of dve in axial patterning and complex process of retinal differentiation, (b) role of dve in delineating eye versus head boundary and (c) genes involved in growth and cancer do have function in patterning and differentiation, (d) How do independent pathways interact to regulate growth and patterning in the developing eye?. These studies will have significant bearings on understanding the (i) molecular basis of developmental defects caused by mutations in the human homolog of Drosophila dve, and (ii) genetic mechanism of early developmental events during organogenesis in higher vertebrates too. In humans and other vertebrates, DV polarity of the retina regulate the retinal axon projections to the brain. These studies will shed light on the role of early developmental events on the retinal axon projection to the brain during normal development and disease. The knowledge generated from these studies is expected to elucidate fundamental mechanisms in patterning and growth of normal visual function and within the context of retinal disease and birth defects in the eye.

在多细胞生物体中，器官单层上皮的转变需要轴向图案通过描绘前后（AP）、背腹（DV）和近远端 (PD) 轴。我们采用果蝇（Drosophila melanogaster）眼睛模型来研究高度（轴向）DV 图案化和生长的基本过程是保守的。在眼睛发育过程中，DV 模式先于 AP 和 PD 轴模式，并形成背侧和腹侧隔室。之间的边界眼睛的背侧和腹侧区域（称为赤道）是 Notch (N) 信号上调的部位，它调节细胞增殖和分化。辨别轴确定（DV）的机制是对于我们理解器官发生至关重要，因为 DV 描绘问题会导致发育/ 果蝇对人类的先天缺陷。我们的长期目标是了解 DV 模式的遗传基础，是通过背侧选择基因和腹侧基因的相互作用建立的。果蝇眼睛开始发育来自腹侧等效状态，在该状态上，背侧命运是通过 GATA 家族表达的开始而确定的转录因子 Pannier (Pnr)、分泌型形态素 Wingless (Wg) 和 Iroquois (Iro-C) 家族蛋白。在背眼中，pnr 不是 Wg 表达的唯一调节因子。它强烈表明可能还有其他尚未确定的背眼基因。为了了解 DV 模式的分子遗传学基础，我们将分析 (1) 确定新的背眼基因 dve 在眼睛发育过程中的作用，(2) 研究背眼图案基因的遗传层次，以及 (3) DV 图案和 Hippo 是否相同信号传导可能在 DV 模式形成过程中共同调节 Wg。鉴于遗传机制是保守的，我们还将测试 SATB1 的作用，SATB1 是眼睛中 dve 的人类直系同源物，已知与生长有关调节、癌症和转移。这些研究将有助于辨别 (a) dve 在轴向图案形成和视网膜分化的复杂过程，(b) dve 在描绘眼睛与头部边界中的作用，(c) 参与生长和癌症的基因确实具有模式和分化的功能，(d) 独立基因如何发挥作用？通路相互作用来调节发育中眼睛的生长和模式？这些研究将具有重大意义关系到理解（i）人类突变引起的发育缺陷的分子基础果蝇 dve 的同源物，以及 (ii) 器官发生过程中早期发育事件的遗传机制高等脊椎动物也是如此。在人类和其他脊椎动物中，视网膜的 DV 极性调节视网膜轴突到大脑的投射。这些研究将揭示早期发育事件对视网膜的作用在正常发育和疾病期间轴突投射到大脑。由这些产生的知识研究有望阐明正常视觉功能模式和生长的基本机制以及视网膜疾病和眼睛先天缺陷的背景下。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An E3 ubiquitin ligase, cullin-4 regulates retinal differentiation in Drosophila eye.

DOI：
10.1002/dvg.23395
发表时间：
2020-11
期刊：
GENESIS
影响因子：
1.5
作者：
Tare, Meghana;Chimata, Anuradha Venkatakrishnan;Gogia, Neha;Narwal, Sonia;Deshpande, Prajakta;Singh, Amit
通讯作者：
Singh, Amit

Motif 1 Binding Protein suppresses wingless to promote eye fate in Drosophila.