Roles of Hox genes in skin and hair follicle development

Hox 基因在皮肤和毛囊发育中的作用

• 批准号: 7206700
• 负责人: ALEXANDER AWGULEWITSCH
• 金额: $ 30.19万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-10 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7206700
• 关键词: A Mouse; Adult; Alleles; Alopecia; Apoptosis; Attention; Binding; Binding Sites; Bioinformatics; Biological Assay; Cadherins; Categories; Cell Proliferation; Classification; Companions; Complex; Congenital Abnormality; Consensus; Consensus Sequence; DNA; DNA Binding; DNA Microarray Chip; DNA Microarray format; Data; Data Set; Defect; Development; Disease; Electrophoretic Mobility Shift Assay; Elements; Embryo; Essential Genes; Exhibits; Family; Future; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Goals; Growth; Hair; Hair Diseases; Hair follicle structure; Hair shaft structure; Human; In Situ Hybridization; In Vitro; Keratin; Knockout Mice; Link; Malignant Neoplasms; Mammals; Mediating; Methods; Microarray Analysis; Mus; Mutate; Mutation; Natural regeneration; Pathway Analysis; Pathway interactions; Pattern; Physiological Processes; Play; Polymerase Chain Reaction; Positioning Attribute; Promoter Regions; Protein Overexpression; Proteins; Proto-Oncogenes; Public Health; Range; Regulation; Regulator Genes; Reporter Genes; Rheumatoid Arthritis; Role; Sampling; Skin; Skin Cancer; Staging; Stem cells; Structural Genes; Testing; Time; Tissue-Specific Gene Expression; Tissues; Transcriptional Regulation; Transfection; Transgenic Mice; Transgenic Organisms; Validation; Wound Healing; appendage; base; chromatin immunoprecipitation; comparative; human disease; in vivo; insight; man; migration; mutant; postnatal; promoter; response; scaffold; skin disorder; tool

DESCRIPTION (provided by applicant): Hox transcriptional regulators play important roles in mammalian development. While their role in the development and regeneration of skin and its appendages is currently understudied, this is receiving increasing attention. A notable case is Hoxc13, which is essential for normal hair follicle development. Both hoxc/3-overexpressing transgenic mice created by us and Hoxc13 null mice exhibit severe hair growth defects resulting in alopecia. DMA microarray analysis of the transgenic mice and subsequent validation by various methods identified Foxql and Foxnl (mutated in nude and satin), proto-oncogene Junb, desmosomal cadherin gene Dsc2, and a several hair keratin genes as putative targets of Hoxc13 regulation. Our results support the hypothesis that Hoxc13 plays a central role in a complex regulatory network controlling hair follicle differentiation. Defining this network is critical for understanding mechanisms involved in numerous skin and hair diseases, including diseases that result in alopecia and some skin cancers. Our overall aims are to 1) determine whether Hoxc13 directly interacts with specific target genes. Control elements will be defined by DNA binding, co-transfection and chromatin immunoprecipitation assays, and Hoxc13-dependent regulation in vivo using reporter gene analysis in both transgenic and null mice. 2) We will determine whether Hoxc13 and Foxgl proteins regulate putative common target genes either cooperatively or independently. We will test functionality of putative Foxql and Hoxc13 binding sites in the promoter region of Dsc2 as a paradigm in vitro, and determine whether these mediate potential cooperative/synergistic responses in co-transfection assays. 3) Lastly, we will define Hoxc13-dependent regulatory gene networks essential for hair follicle differentiation. Comparative longitudinal DNA microarray analysis will be done using skin samples from both transgenic and null mice with appropriate controls at 5 time points. These data will define the effect of over- or nonexpression of Hoxc13 at distinct morphogenetic stages of hair follicle development. Use of Ingenuity Network Analysis(c) and other bioinformatics tools will allow us to develop a conceptual framework of a Hoxc13-controlled genetic network regulating hair follicle differentiation. Relevance to Public Health: We are defining a gene network that controls development of hair follicles and hair shafts in mammals. Mutations in any or all of these genes result in a various types of alopecia, many of which are identical to specific human skin diseases. Our goal is to determine how these genes interact with each other, which will ultimately define how these diseases can be approached therapeutically.

描述（由申请人提供）：Hox 转录调节因子在哺乳动物发育中发挥重要作用。虽然它们在皮肤及其附属器的发育和再生中的作用目前尚未得到充分研究，但这一点正受到越来越多的关注。一个值得注意的例子是 Hoxc13，它对于正常毛囊发育至关重要。我们创建的 hoxc/3 过表达转基因小鼠和 Hoxc13 缺失小鼠均表现出严重的毛发生长缺陷，导致脱发。对转基因小鼠的 DMA 微阵列分析以及随后通过各种方法进行的验证确定了 Foxql 和 Foxnl（在裸色和缎纹中突变）、原癌基因 Junb、桥粒钙粘蛋白基因 Dsc2 和一些毛发角蛋白基因作为 Hoxc13 调节的推定靶标。我们的结果支持这样的假设：Hoxc13 在控制毛囊分化的复杂调控网络中发挥核心作用。定义这个网络对于理解涉及多种皮肤和毛发疾病的机制至关重要，包括导致脱发和一些皮肤癌的疾病。我们的总体目标是 1) 确定 Hoxc13 是否直接与特定靶基因相互作用。控制元件将通过 DNA 结合、共转染和染色质免疫沉淀测定以及使用转基因小鼠和无效小鼠中的报告基因分析进行体内 Hoxc13 依赖性调节来定义。 2）我们将确定Hoxc13和Foxgl蛋白是否协同或独立调节假定的共同靶基因。我们将测试 Dsc2 启动子区域中假定的 Foxql 和 Hoxc13 结合位点的功能作为体外范例，并确定这些是否在共转染测定中介导潜在的协同/协同反应。 3）最后，我们将定义对毛囊分化至关重要的Hoxc13依赖性调控基因网络。将使用来自转基因小鼠和无效小鼠的皮肤样本以及在5个时间点的适当对照来进行比较纵向DNA微阵列分析。这些数据将定义 Hoxc13 过度表达或不表达在毛囊发育的不同形态发生阶段的影响。使用 Ingenuity Network Analysis(c) 和其他生物信息学工具将使我们能够开发一个由 Hoxc13 控制的调节毛囊分化的遗传网络的概念框架。与公共卫生的相关性：我们正在定义一个控制哺乳动物毛囊和毛干发育的基因网络。任何或所有这些基因的突变都会导致各种类型的脱发，其中许多与特定的人类皮肤病相同。我们的目标是确定这些基因如何相互作用，这将最终确定如何治疗这些疾病。