Signaling Pathways in Skin Patterning and Polarity

皮肤图案和极性中的信号通路 项目摘要 发育生物学的一个主要挑战是了解单细胞如何与一个 另一个用于建立它们相对于组织和身体轴的取向。邻区协调 细胞在组织平面内的极性称为组织极性或平面细胞极性（PCP）。PCP参与各种 五氯苯酚的缺陷会导致人类的许多发育障碍。 越来越多的证据还表明，五氯苯酚与某些癌症有关。我们研究的长期目标是 是揭示哺乳动物PCP在正常发育和疾病中的基本机制。在这 建议，我们解决了几个悬而未决的中心问题，在PCP领域阐明机制 Frizzled6（Fz6）是一种控制小鼠皮肤极性的关键膜PCP蛋白。初步 研究发现：（1）Fz配体Wnt家族成员Wnt 5a的过表达 受体，破坏毛囊方向;（2）敲除Fz6导致显著的转录变化 （3）Astrotactin-2（Astn2），最近鉴定的Fz6的遗传修饰剂，结合到皮肤中的Fz3和Fz6， 体外基于现有文献和我们的初步数据，我们假设Astn 2是 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测试我们的假设与以下三个目标：（1）以确定是否 Wnt配体，特别是Wnt5a，在Fz6介导的皮肤PCP中起定向线索的作用;（2）阐明 调控Fz6介导的皮肤PCP的转录机制;以及（3）阐明Astn2的机制 修饰Fz6基因敲除小鼠的皮肤极性缺陷。该研究具有创新性。我们将 联合收割机结合了我们已经产生的独特的小鼠模型和我们拥有的一种新的体外PCP系统， 旨在阐明Fz6在皮肤PCP中的作用机制。所提出的研究是有意义的。的 aims将揭示Fz6介导的PCP途径中几个新组分的机制见解， 包括上游配体、辅因子和下游效应物。由于五氯苯酚是一种基本的、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，囊性 肾病、听力丧失、纤毛病变和心脏缺陷。

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.