Hox Regulation of Sensory Organ Development in Drosophila

果蝇感觉器官发育的 Hox 调控

基本信息

批准号：
7771709
负责人：
BRIAN GEBELEIN
金额：
$ 28.22万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7771709
关键词：
Abdomen Address Afferent Neurons Affinity Animal Model Anterior Binding Binding Sites Biochemical Genetics Bioinformatics Biological Assay Biological Models Blood Blood Cells Cell Culture System Cells Complex Computer Systems Development Consensus Coupled DNA Binding Development Developmental Biology Disease Drosophila genus Embryo Enhancers Epidermal Growth Factor Equilibrium Gene Activation Gene Expression Gene Expression Regulation Gene Targeting Genes Genetic Genetic Transcription Goals Grant Growth Factor Hearing Helix-Turn-Helix Motifs Hepatocyte Histocompatibility Testing Homologous Gene Human Development Hybrids Laboratories Ligands Location Luciferases Maps Mediating Molecular Mus Mutation Nervous system structure Neuronal Differentiation Neurons Nucleotides Organ Organism POU domain factors Pathway interactions Pattern Peptide Hydrolases Positioning Attribute Process Proprioception Proteins Regulation Reporter Repression Role Sensory Sequence Analysis Series Signal Transduction Site Specific qualifier value Specificity Testing Tissues To specify Transgenic Organisms Vertebrates Vision Yeasts Zinc Fingers comparative fly gene repression in vivo insight leukemia neuron development novel precursor cell public health relevance relating to nervous system research study rho rhomboid tool transcription factor

项目摘要

DESCRIPTION (provided by applicant): How cells interpret positional information to properly differentiate and form distinct tissues and organs is a fundamental problem in developmental biology. In the nervous system, for example, numerous neuronal subtypes and sensory organs form at precisely defined positions. The long-term goal of this proposal is to understand how anterior- posterior positional information provided by Hox transcription factors is combined with neuronal differentiation pathways to dictate the type, number, and location of different neurons and sensory organs in the body. Using Drosophila as a model organism, we are focused on understanding how a specific Hox factor, Abdominal-A (Abd-A), modulates sensory organ formation by activating rhomboid (rho). rho encodes a protease that processes an epidermal growth factor (EGF) ligand to induce additional neurons and a set of hepatocyte-like cells. Through bioinformatics and transgenic reporter assays, we identified two Hox-regulated rho enhancers expressed in a specific subset of abdominal sensory neurons. The biochemical and genetic characterization of a conserved enhancer region uncovered a novel mechanism used by Hox factors and their conserved co-factors Extradenticle (Exd) and Homothorax (Hth) to stimulate gene expression: Abd- A antagonizes transcriptional repression by Senseless (Sens), a neuronal zinc finger protein, through direct competition for DNA binding sites. Sens and its vertebrate homologues Growth factor independence-1 (Gfi1) are critical regulators of sensory organ development in both the fly and mouse. We hypothesize that Hox-Sens antagonism is a general mechanism of gene regulation. This hypothesis as well as the identification of other Hox-neuronal transcription factor interactions will be tested in the following aims: 1) Determine the mechanisms used by Abd-A to stimulate rho, 2) Test the role of Hox- Sens competition in the regulation of gene expression, and 3) Identify additional neuronal inputs that regulate rho in ch organ SOP cells. These experiments take advantage of genetic tools available in Drosophila, which unlike in the vertebrate, contain a single set of non-redundant Hox factors. In addition to controlling neuronal development, the Hox, Exd, Hth, and Sens vertebrate homologues all regulate blood cell formation and have been implicated in leukemia. Thus, the Hox and Sens/Gfi1 molecular mechanisms uncovered in this grant are relevant to human development and disease. Public Health Relevance: We have identified two factors that regulate nervous and blood system development. This grant is focused on how these factors function to specify sensory organs using the fruit fly as a model system. As both factors have been implicated in leukemia, our studies are likely to shed new insight into both Human development and disease.

描述（由申请人提供）：细胞如何解释位置信息正确区分和形成不同的组织和器官是发育生物学的基本问题。在神经系统中，例如，精确定义的位置形成了许多神经元亚型和感觉器官。该提案的长期目标是了解HOX转录因子提供的前后位置信息如何与神经元分化途径相结合，以决定体内不同神经元和感觉器官的类型，数量和位置。使用果蝇作为模型生物，我们专注于了解特定的HOX因子腹部A（ABD-A）如何通过激活菱形（RHO）调节感觉器官形成。 RHO编码一种处理表皮生长因子（EGF）配体以诱导其他神经元和一组肝细胞样细胞的蛋白酶。通过生物信息学和转基因报告基因测定，我们确定了在腹部感觉神经元特定子集中表达的两个HOX调节的RHO增强子。保守增强子区域的生化和遗传表征发现了HOX因子及其保守的辅助因子（EXD）和同胸（HTH）（HTH）使用的一种新机制，以刺激基因表达：ABD- A ABD-A ABD-ABD-A ABD A ABD-ABD A ABD-ASSIND CORMINAL（SENS）通过神经Zinc Finger Protein comportes进行dna Comportes dna imante comportes dna thement seenscriptions抑制作用（sens）。 SENS及其脊椎动物同源物生长因子独立1（GFI1）是蝇和小鼠感觉器官发育的关键调节剂。我们假设Hox-Sens拮抗作用是基因调节的一般机制。在以下目的中将测试该假设以及对其他HOX - 神经转录因子相互作用的鉴定：1）确定ABD-A用于刺激RHO的机制，2）测试HOX-SENS竞争在基因表达调控中的作用，3）识别调节Rho CH Orn ChO Orner ChO Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organ Organsop Organsop Organsop sop sop sop sop sop sop。这些实验利用了果蝇中可用的遗传工具，与脊椎动物不同，这些工具包含一组非冗余的HOX因子。除了控制神经元发育外，HOX，EXD，HTH和SENS脊椎动物同源物都调节血细胞的形成，并与白血病有关。因此，本赠款中发现的HOX和SENS/GFI1分子机制与人类发育和疾病有关。公共卫生相关性：我们确定了调节神经系统发展的两个因素。该赠款的重点是这些因素如何使用果蝇作为模型系统来指定感觉器官。由于这两个因素都与白血病有关，因此我们的研究可能会给人类发展和疾病提供新的见解。