WNT signals in skin and hair development and hair growth

皮肤和毛发发育以及毛发生长中的 WNT 信号

• 批准号: 7193377
• 负责人: Sarah E. Millar
• 金额: $ 33.65万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2011-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7193377
• 关键词: Adaptor Signaling Protein; Architecture; Binding; Biological Assay; Cell Communication; Cell Polarity; Cells; Complex; Data; Development; Dominant-Negative Mutation; Elements; Embryo; Embryonic Development; Epithelial; Epithelial Cells; Epithelium; Family member; Gene Activation; Genes; Growth; Growth Disorders; Growth and Development function; Hair; Hair Follicle Neoplasm; Hair follicle structure; Ligands; Maintenance; Mediating; Mesenchymal; Morphogenesis; Movement; Mus; Mutant Strains Mice; Mutation; Natural regeneration; Pathway interactions; Phase; Phenotype; Plant Roots; Play; Proteins; Research Personnel; Role; Signal Pathway; Signal Transduction; Site; Skin; Testing; Transcript; Transgenic Mice; Transgenic Organisms; Tumor Necrosis Factor Receptor; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; WNT Signaling Pathway; Wound Healing; appendage; beta catenin; cell motility; chromatin immunoprecipitation; ectodysplasin; human TNF protein; in vivo; inhibitor/antagonist; keratinocyte; mouse crinkled protein; mouse model; mutant; novel; paracrine; postnatal; programs; promoter; receptor; research study

DESCRIPTION (provided by applicant): Cell-cell communication is essential to the development and function of the skin and its appendages. We discovered that the canonical WNT/beta-catenin intercellular signaling pathway is required for initiating the formation of all types of hair follicle placodes during embryogenesis, and is essential postnatally for hair growth. These findings have potential significance for the development of strategies for regenerating hair follicles in cases of congenital absence or loss, and for the treatment of hair growth disorders. However, as activating mutations in beta-catenin can cause hair follicle tumors, it will be of critical importance to delineate the precise mechanisms by which WNT/beta-catenin signals normally initiate hair follicle development and regulate postnatal hair growth, and to identify the WNT ligands that control normal development and growth. To these ends we will test the hypothesis that WNT/beta-catenin signaling initiates hair follicle morphogenesis by direct activation of genes of the tumor necrosis factor (TNF) and TNF receptor familes. We will manipulate WNT/beta-catenin signaling in inducible transgenic mouse models to determine the requirement for this pathway for the onset and maintenance of the anagen phase of the hair growth cycle, and we will examine the skin phenotypes of mice mutant for two hair follicle-expressed Wnt genes. Unexpectedly, we discovered that expression of Frizzled WNT receptors in developing and postnatal skin is not confined to sites of known activity of the WNT/beta-catenin pathway, suggesting that WNT signaling through alternate pathways may contribute to the development and maintenance of the skin and hair follicles. Non-canonical WNT signaling regulates the planar cell polarity of epithelial cells and cell movements in vertebrate embryos. We will test the hypothesis that non-canonical WNT signaling is important for cell movements and polarity in skin epithelia by depleting the function of a key non-canonical WNT signaling pathway component in mouse skin in vivo and in cultured keratinocyes.

描述（由申请人提供）：细胞电池通信对于皮肤及其附属物的发育和功能至关重要。我们发现，在胚胎发生过程中启动所有类型的毛囊姿势需要启动所有类型的毛囊姿势需要规范的Wnt/beta-catenin间信号通路，这对于毛发生长来说是必不可少的。这些发现对于在先天性缺勤或损失的情况下以及治疗毛发障碍的情况下，为制定再生毛囊的策略具有潜在的意义。但是，由于β-蛋白的激活突变会引起毛囊肿瘤，因此描述Wnt/beta-catenin信号通常会启动毛囊发育并调节产后毛发生长的确切机制至关重要，并确定控制正常发育和生长的WNT。为此，我们将测试以下假设：Wnt/beta-catenin信号传导通过直接激活肿瘤坏死因子（TNF）和TNF受体家族的基因来启动毛囊形态发生。我们将操纵可诱导的转基因小鼠模型中的Wnt/β-catenin信号传导，以确定该途径的要求和维持头发生长周期的Anagen阶段的需求，我们将检查小鼠突变体对两个毛卵泡表达的Wnt基因的皮肤表型。出乎意料的是，我们发现在发育和产后皮肤中卷曲的Wnt受体的表达不仅限于Wnt/beta-catenin途径的已知活性部位，这表明通过替代途径的Wnt信号传导可能有助于皮肤和毛囊的发育和维持。非典型的Wnt信号传导调节脊椎动物胚胎中上皮细胞和细胞运动的平面细胞极性。我们将测试以下假设：非典型的Wnt信号传导通过耗尽了体内小鼠皮肤和培养的角质分析中关键的非典型Wnt信号通路的功能，对皮肤上皮的细胞运动和极性很重要。