Signaling Pathways in Skin Patterning and Polarity

皮肤图案和极性的信号通路

基本信息

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
项目类别：
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

项目摘要

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.

皮肤模式和极性的信号传导途径项目概要发育生物学的一个主要挑战是了解单细胞如何与一个细胞协调另一个是确定它们相对于组织和身体轴的方向。邻里协调组织平面上的细胞称为组织极性或平面细胞极性（PCP）。 PCP 参与各种 PCP 的发育过程和缺陷会导致人类许多发育障碍。越来越多的证据还表明五氯苯酚与某些癌症有关。我们学习的长期目标旨在揭示哺乳动物PCP在正常发育和疾病中的基本机制。在这个提案中，我们通过阐明机制来解决 PCP 领域中几个未解答的核心问题 Frizzled6 (Fz6) 是一种控制小鼠皮肤极性的关键膜 PCP 蛋白。在初步研究中，我们发现：（1）Wnt5a 过度表达，Wnt5a 是 Fz 配体 Wnt 家族的成员受体，破坏毛囊方向； (2)敲除Fz6导致显着的转录变化在皮肤中； (3) Astrotactin-2 (Astn2) 是最近发现的一种 Fz6 遗传修饰剂，可与 Fz3 和 Fz6 结合体外。根据现有文献和我们的初步数据，我们假设 Astn2 是皮肤中的 Wnt5a-Fz6 信号传导 PCP 和 Fz6 调节先前未定义的转录网络建立皮肤极性。我们将通过以下三个目标来检验我们的假设：（1）确定是否 Wnt 配体，尤其是 Wnt5a，在 Fz6 介导的皮肤 PCP 中充当定向线索； (2) 阐明控制 Fz6 介导的皮肤 PCP 的转录机制； (3) 阐明 Astn2 的机制改变 Fz6 敲除小鼠的皮肤极性缺陷。拟议的研究具有创新性。我们将将我们生成的独特小鼠模型与我们拥有的新型体外 PCP 系统相结合旨在阐明 Fz6 在皮肤 PCP 中的作用机制。拟议的研究意义重大。这目标将揭示 Fz6 介导的 PCP 途径中几个新组件的机制见解，包括上游配体、辅助因子和下游效应子。由于 PCP 是基本的、保守的调节广泛的发育过程的途径，这些数据也将改善我们的了解 PCP 相关疾病的发病机制，如开放性神经管、腭裂、囊肿等肾脏疾病、听力损失、纤毛病和心脏缺陷。