Signaling Pathways in Skin Patterning and Polarity

皮肤花纹和极性中的信号通路 项目总结 发育生物学中的一个主要挑战是了解单个细胞是如何与一个 另一种是确定它们相对于组织和身体轴线的方向。邻域的协调 组织平面上的细胞称为组织极性或平面细胞极性(PCP)。PCP参与了各种 发育过程中，五氯苯酚的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。我们研究的长期目标是 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 建议，我们通过阐明机制来解决PCP领域中几个悬而未决的核心问题 Frizzled6(FZ6)是一种关键的膜PCP蛋白，控制小鼠皮肤的极性。在预赛中 研究发现：(1)FZ配体Wnt家族成员Wnt5a的过表达 受体，破坏毛囊的方向；(2)敲除FZ6导致显著的转录变化 (3)Astrotactin-2(ASTN2)，一种新近发现的FZ6的遗传修饰物，与FZ3和FZ6结合。 体外培养。根据现有的文献和我们的初步数据，我们假设ASTN2是 皮肤PCP和FZ6中的Wnt5A-FZ6信号调节先前未定义的转录网络 来建立皮肤的极性。我们将通过以下三个目标来检验我们的假设：(1)确定 Wnt配体，尤其是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 在修改FZ6基因敲除小鼠的皮肤极性缺陷方面。提出的研究具有创新性。我们会 将我们建立的独特的小鼠模型与我们拥有的一种新的体外PCP系统相结合 为阐明FZ6在皮肤PCP中的作用机制而开发。这项拟议的研究具有重要意义。这个 AIMS将揭示FZ6介导的PCP途径中的几个新组成部分的机械学见解， 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，如神经管开放、腭裂、囊性 肾脏疾病、听力损失、纤毛疾病和心脏缺陷。

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.