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Molecular Genetics of Segment Identity

片段同一性的分子遗传学

基本信息

批准号：
8330971
负责人：
RICHARD S MANN
金额：
$ 4万
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/8330971
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novel paralogous gene public health relevance research study three dimensional structure tool transcription factor unpublished works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）：