Molecular Genetics of Segment Identity

片段同一性的分子遗传学

基本信息

批准号：
7590425
负责人：
RICHARD S MANN
金额：
$ 35.3万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-08-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7590425
关键词：
Abdomen Animals Anterior Base Pairing Binding Sites Biochemistry Biological Biological Assay Biological Models Biology Cell Maintenance Cell Proliferation Complex Congenital Abnormality DNA DNA Binding DNA Structure DNA-Protein Interaction Development Disease Drosophila genus Drosophila inturned protein Drosophila melanogaster Equilibrium Family Funding Gene Expression Regulation Gene Targeting Genes Genetic Goals Homeodomain Proteins Human In Vitro Limb structure Malignant Neoplasms Maps Mediating Minor Groove Modeling Molecular Genetics Morphology Motor Neurons Organ Organogenesis Orthologous Gene Pathway interactions Pattern Play Protein Binding Proteins Publishing Reading Recruitment Activity Regulation Regulatory Element Resolution Role Signal Pathway Specificity Stem cells System Testing Vertebrates Wing Work X-Ray Crystallography appendage base cofactor design fascinate homeodomain in vivo interest leukemia malformation morphogens motor neuron development novel paralogous gene public health relevance research study three dimensional structure tool transcription factor unpublished works

项目摘要

DESCRIPTION (provided by applicant): The Hox family of transcriptional regulators are homeodomain proteins that play important roles in many aspects of animal development and disease. For these proteins to perform their functions, they need to achieve the correct functional specificities in vivo. Using the fruit fly, Drosophila melanogaster, as the model system, this project builds on earlier work to better understand how these transcriptional regulators function in vivo. In previous work, results were obtained suggesting that Hox proteins, in conjunction with cofactors of the Extradenticle (Exd, Pbx in vertebrates) and Homothorax (Hth; Meis in vertebrates) families, achieve DNA binding specificity by reading a sequence-dependent DNA structure using residues in their homeodomains and nearby linker regions. A second set of findings demonstrated that some Hox proteins interact with these cofactors via multiple, partially redundant interaction motifs. Third, results were obtained showing that one Hox protein in Drosophila, Ultrabithorax (Ubx), modifies appendage morphologies, in particular, appendage size, by altering the levels and mobilities of diffusible morphogens such as Decapentaplegic (Dpp). Ubx executes these modfications in part by transcriptionally regulating two genes, master of thickveins (mtv) and dally in the developing appendage. Building on these results, the aims of this project are to 1) extend and generalize the Exd-dependent Hox specificity model, 2) determine the role of multiple Exd interaction motifs that are present in some Hox proteins, and 3) determine which of the targets identified previously in the control of appendage morphology by Ubx are directly regulated by this Hox protein. The approaches for all of these aims rely heavily on using a combination of Drosophila genetic tools and in vitro protein-DNA interaction assays. X-ray crystallography, to determine the three dimensional structures of some Hox-Exd-DNA ternary complexes, will also be employed. Public Health Relevance: Although first analyzed in the context of anterior-posterior patterning, there are a wealth of critical functions in animal development from motor neuron specification to organogenesis to stem cell maintenance that are now appreciated to be controlled by Hox genes. Equally important and well studied are the roles that Hox genes and their cofactors play in human birth defects, such as limb malformations, and some cancers, such as leukemia. Thus, a mechanistic understanding of how these transcription factors regulate their target genes will impact our understanding of many aspects of developmental and disease biology.

描述（由申请人提供）： HOX转录调节剂家族是同源域蛋白，在动物发育和疾病的许多方面起重要作用。为了使这些蛋白质执行其功能，需要在体内实现正确的功能特异性。使用果蝇，果蝇Melanogaster作为模型系统，基于早期工作，以更好地了解这些转录调节器如何在体内发挥作用。在先前的工作中，获得了结果，表明HOX蛋白与内部（EXD，脊椎动物中的PBX，PBX）和同胸（HTH; Meis in Certebrates in pertebrates）家族的辅助因子结合使用，通过阅读序列依赖性DNA结构在其同源层和接近的Linkererain和附近的Linkererions中获得DNA结合特异性，从而实现DNA结合特异性。第二组发现表明，某些HOX蛋白通过多个，部分冗余的相互作用基序与这些辅助因子相互作用。第三，获得的结果表明，果蝇（UBX）中的一种HOX蛋白质通过更改可扩散形态的水平和迁移率（如脱皮术（DPP））来修饰附属形态，特别是附属物大小。 UBX通过转录调节两个基因（MTV）（MTV）和Dally在发育的附属物中执行这些调节作用。在这些结果的基础上，该项目的目的是1）扩展并推广依赖于EXD的HOX特异性模型，2）确定某些HOX蛋白中存在的多个EXD相互作用基序的作用，3）确定以前确定的靶标在UBX控制UBX中由该HOX蛋白直接调节了附加形态。所有这些目的的方法在很大程度上依赖于果蝇遗传工具和体外蛋白-DNA相互作用测定法的结合。还将采用X射线晶体学，以确定某些HOX-EXD-DNA三元复合物的三维结构。公共卫生相关性：尽管首先在前后形式的背景下进行了分析，但动物发育中有很多关键功能从运动神经元规范到器官发生到干细胞维持，现在被认为由HOX基因控制。同样重要且研究良好的是Hox基因及其辅助因子在人类出生缺陷中所扮演的角色，例如肢体畸形，以及一些癌症，例如白血病。因此，对这些转录因子如何调节其靶基因的机械理解将影响我们对发育和疾病生物学许多方面的理解。