Signaling Pathways in Skin Patterning and Polarity

皮肤图案和极性的信号通路

• 批准号: 10393531
• 负责人: Hao Chang
• 金额: $ 32.66万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10393531
• 关键词: Address; Affect; Alkaline Phosphatase; Alleles; Binding; Biological Assay; Cells; Cleft Palate; Co-Immunoprecipitations; Cues; Cystic Kidney Diseases; Cytokeratin; Data; Defect; Development; Developmental Biology; Developmental Process; Disease; Family; Genes; Genetic; Genetic Transcription; Genetic study; Goals; Hair follicle structure; Heart Abnormalities; Human; In Vitro; Knock-out; Knockout Mice; Ligands; Link; Literature; Maintenance; Malignant Neoplasms; Mediating; Membrane; Microfluidic Microchips; Mosaicism; Mus; Neural Tube Defects; Neural tube; Neuraxis; Organ; Pathogenesis; Pathway interactions; Pattern; Phenotype; Polycystic Kidney Diseases; Proteins; Proteomics; Research; Role; Series; Side; Signal Pathway; Signal Transduction; Skin; System; Testing; Tissues; Transgenic Organisms; base; ciliopathy; cofactor; congenital heart disorder; deafness; developmental disease; experimental study; hearing impairment; human data; human disease; improved; in vitro testing; innovation; insight; keratinocyte; loss of function; member; mouse model; nervous system development; novel; overexpression; planar cell polarity; receptor; receptor recycling; relating to nervous system; rho; trafficking; transcriptome; transcriptomics

SIGNALING PATHWAYS IN SKIN PATTERNING AND POLARITY PROJECT SUMMARY A major challenge in developmental biology is to understand how single cells are coordinated with one another to establish their orientations with respect to tissue and body axes. The coordination of neighboring cells in the plane of tissue is called tissue polarity or planar cell polarity (PCP). PCP is involved in various developmental processes, and defects in PCP cause many developmental disorders in humans. Increasing evidence also suggests that PCP is involved in certain cancers. The long-term goal of our study is to uncover fundamental mechanisms of mammalian PCP in normal development and disease. In this proposal, we address several unanswered central questions in the PCP field by elucidating mechanisms of Frizzled6 (Fz6), a key membrane PCP protein that controls the polarity of mouse skin. In preliminary studies, we discovered: (1) overexpression of Wnt5a, a member of the Wnt family of ligands for Fz receptors, disrupts hair follicle orientations; (2) knockout of Fz6 results in significant transcriptional changes in the skin; (3) Astrotactin-2 (Astn2), a recently identified genetic modifier of Fz6, binds to Fz3 and Fz6 in vitro. Based on available literature and our preliminary data, we hypothesize that Astn2 is a cofactor for Wnt5a-Fz6 signaling in skin PCP and Fz6 regulates a previously undefined transcriptional network to establish skin polarity. We will test our hypothesis with the following three aims: (1) to determine if Wnt ligands, especially Wnt5a, function as orienting cues in Fz6-mediated skin PCP; (2) to elucidate transcriptional mechanisms governing Fz6-mediated skin PCP; and (3) to elucidate mechanisms of Astn2 in modifying the skin polarity defect in Fz6 knockout mice. The proposed research is innovative. We will combine unique mouse models that we have generated and a novel in vitro PCP system that we have developed to elucidate the mechanisms of Fz6 in skin PCP. The proposed research is significant. The aims will unveil mechanistic insights into several new components in the Fz6-mediated PCP pathway, including upstream ligands, cofactors, and downstream effectors. Since PCP is a fundamental, conserved pathway that regulates a wide range of developmental processes, these data will also improve our understanding of the pathogenesis of PCP-related diseases, such as open neural tube, cleft palate, cystic kidney disease, hearing loss, ciliopathies, and heart defects.

皮肤图案和极性的信号通路 项目摘要 发育生物学的主要挑战是了解单个细胞如何与一个细胞协调 另一个是建立有关组织和身体轴的方向。邻国的协调 组织平面中的细胞称为组织极性或平面细胞极性（PCP）。 PCP参与了各种 发育过程和PCP缺陷会导致人类的许多发育障碍。 越来越多的证据也表明PCP参与了某些癌症。我们研究的长期目标 是要发现哺乳动物PCP在正常发育和疾病中的基本机制。在这个 提案，我们通过阐明机制来解决PCP领域中的几个未解决的中心问题 毛躁6（FZ6）的含量，这是一种控制小鼠皮肤极性的关键膜PCP蛋白。在初步 研究，我们发现：（1）Wnt5a的过表达，Wnt5a是Fz的Wnt家族的成员 受体，破坏毛囊取向； （2）FZ6的敲除导致重大转录变化 在皮肤中； （3）Astrotactin-2（ASTN2）是最近鉴定出的FZ6的遗传修饰剂，与Fz3和Fz6结合 体外。基于可用文献和我们的初步数据，我们假设ASTN2是辅助因子 皮肤PCP和FZ6中的WNT5A-FZ6信号传导调节先前未定义的转录网络 建立皮肤极性。我们将以以下三个目的测试我们的假设：（1）确定是否是否 Wnt配体，尤其是Wnt5a，在FZ6介导的皮肤PCP中起定向线索； （2）阐明 控制FZ6介导的皮肤PCP的转录机制； （3）阐明ASTN2的机制 在修饰FZ6基因敲除小鼠中的皮肤极性缺陷时。拟议的研究是创新的。我们将 结合了我们已经生成的独特鼠标模型和一种新型的体外PCP系统 开发旨在阐明皮肤PCP中FZ6的机制。拟议的研究很重要。这 Aims将在FZ6介导的PCP途径中揭示对几个新组件的洞察力， 包括上游配体，辅助因子和下游效应子。由于PCP是一个基本的，保守的 规范广泛发展过程的途径，这些数据也将改善我们的 了解与PCP相关疾病的发病机理，例如开放神经管，唇裂，囊性 肾脏疾病，听力丧失，纤毛病和心脏缺陷。