Wnt/Frizzled-PCP signaling in development and disease

发育和疾病中的 Wnt/Frizzled-PCP 信号传导

基本信息

批准号：
10159276
负责人：
Marek Mlodzik
金额：
$ 60.75万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10159276
关键词：
Address Adult Affect Apical Binding Biochemical Biological Cell Culture Techniques Cell Polarity Cell division Cells Cellular biology Cilia Data Defect Development Disease Dissection Drosophila genus Epithelial Epithelial Cells Goals Homeostasis Infertility Labyrinth Ligands Link Maintenance Malignant Neoplasms Mammals Medical Molecular Mutation Neural Tube Closure Organ Organogenesis Pathway interactions Patients Pattern Phosphorylation Phosphotransferases Physiological Positioning Attribute Process Proteins Proto-Oncogenes Regulation Research Respiratory System Signal Transduction Skin Specificity Structure Tissues Tumor Suppressor Proteins Work base beta catenin ciliopathy convergent extension deafness experimental study gastrulation human disease in vivo member organ growth planar cell polarity polarized cell receptor response stem cells

项目摘要

Epithelial cells are polarized in two axes for their function, ubiquitous apical-basal polarity and a second axis within the epithelial plane, referred to as Planar Cell Polarity (PCP). Cell polarity and ordered cellular patterning during organ development and homeostasis depend on PCP mechanisms. Classical PCP examples include in Drosophila adult cuticular structures. Similarly, in mammals striking aspects of PCP are evident in the skin, the inner ear epithelium, or the respiratory system and most other internal organs. Moreover, convergent extension processes during gastrulation and neural tube closure requires PCP signaling, and the PCP pathway is linked to the regulation of asymmetric cell divisions in stem cells of many organs. Studies of PCP establishment in Drosophila serve as a paradigm to unravel this type of polarity in development and human disease. PCP is coordinated by long-range Wnt ligand signals, resulting in asymmetric localization of their receptors, the Frizzled (Fz) proteins, and associated signaling cascade. Core Fz/PCP factors are required to interpret polarity within the cell and relay this to neighboring cells. All core Fz/PCP members are evolutionarily conserved and regulate all PCP aspects. This Wnt-pathway is distinct from canonical Wnt-Fz/β-catenin signaling (and correct regulation of signaling specificity between the two Wnt-pathways, activated by the same receptor(s), is critical for development and disease). In Wnt-PCP-signaling Fz's act both, as receptors for Wnts and ligands for its intercellular binding partner(s) Van Gogh/Vang (Vangl1/2 in mammals). The cellular mechanism(s) affecting polarity downstream of either Fz or Vang upon polarized localization remain very poorly understood. The scope and focus of my lab's research and this application is to investigate the mechanistic interactions of long-range PCP signaling and the resulting cell biological read-outs and intracellular responses. Our recent focus has been/is on Vang/Vangl function, as a result of its intercellular interaction with Fz, and the associated cellular response. Our work is and will be also guided by patient derived data and the respective functional dissection of these mutations. Based on exciting ongoing experiments, we will address the physiological significance of Fz-induced Vang phosphorylation and associated kinase function, and how these affect Vang interactions with cytoplasmic effectors. These studies will be aided by including patient data with Vangl1/2 associated neural tube closure defects. In parallel, we are dissecting the intracellular cell biological responses to PCP signaling and how these affect positioning and the mechanistic interplay with cilia associated proteins, with the advantage of being able to do so in non-ciliated Drosophila cells. A combination of in vivo studies and cell culture biochemical experiments will be performed to achieve these goals. The processes of PCP establishment and Wnt/Fz signaling have been linked to several medical abnormalities, ranging from deafness to neural tube closure defects and cancer, or ciliopathies in general. Information acquired will advance our understanding of cellular polarization, and provide medical relevance in many disease contexts.

上皮细胞因其功能而在两个轴上极化，即普遍存在的顶端-基底极性和第二个轴上皮平面内的细胞极性，称为平面细胞极性（PCP）。器官发育和体内平衡依赖于 PCP 机制经典的 PCP 例子包括类似地，果蝇成体的角质层结构在哺乳动物中的皮肤中也很明显。内耳上皮，或呼吸系统和大多数其他内脏器官。原肠胚形成和神经管闭合期间的过程需要 PCP 信号传导，并且 PCP 通路是相连的许多器官干细胞不对称细胞分裂的调节 PCP 建立的研究。果蝇是揭示发育和人类疾病中这种极性的范例。由长程 Wnt 配体信号协调，导致其受体的不对称定位，卷曲 (Fz) 蛋白和相关信号级联是解释极性所必需的。所有核心 Fz/PCP 成员在进化上都是保守的，并且将其传递给相邻的细胞。该 Wnt 通路与典型的 Wnt-Fz/β-连环蛋白信号传导不同（并且是正确的）。由相同受体激活的两条 Wnt 通路之间信号传导特异性的调节至关重要在 Wnt-PCP 信号传导中，Fz 既作为 Wnt 的受体又作为其配体。细胞间结合伴侣 Van Gogh/Vang（哺乳动物中的 Vangl1/2）影响细胞机制。极化定位时 Fz 或 Vang 下游的极性仍然知之甚少。我的实验室研究和此应用的重点是研究远程的机械相互作用 PCP 信号传导以及由此产生的细胞生物学读数和细胞内反应。由于其与 Fz 的细胞间相互作用以及相关的细胞因子，Vang/Vangl 功能一直/正在发挥作用我们的工作现在和将来都以患者数据和相应的功能解剖为指导。基于令人兴奋的正在进行的实验，我们将探讨这些突变的生理意义。 Fz 诱导的 Vang 磷酸化和相关激酶功能，以及这些如何影响 Vang 与这些研究将通过纳入 Vangl1/2 相关神经的患者数据来帮助。与此同时，我们正在剖析细胞内细胞对 PCP 信号传导的生物反应。以及这些如何影响定位以及与纤毛相关蛋白的机械相互作用，能够在非纤毛果蝇细胞中做到这一点的优势是体内研究和细胞研究的结合。将进行培养生化实验以实现这些目标。建立和 Wnt/Fz 信号传导与多种医学异常有关，包括耳聋神经管闭合缺陷和癌症或纤毛病的总体信息将促进我们的研究。了解细胞极化，并提供许多疾病背景下的医学相关性。