Wnt/Frizzled-PCP signaling in development and disease

发育和疾病中的 Wnt/Frizzled-PCP 信号传导

• 批准号: 9912774
• 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
• 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/9912774
• 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; Epithelium; 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

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.

上皮细胞的极化有两个轴，一个是普遍存在的顶端-基底极性，另一个是第二轴 在上皮平面内，称为平面细胞极性（PCP）。细胞极性和有序的细胞模式 器官发育和体内平衡取决于PCP机制。经典的PCP示例包括 果蝇成虫表皮结构。同样，在哺乳动物中，五氯苯酚的显著特征在皮肤、 内耳上皮，或呼吸系统和大多数其他内部器官。此外，收敛扩张 在原肠胚形成和神经管关闭过程中需要PCP信号，PCP通路与 调节许多器官干细胞的不对称细胞分裂。五氯苯酚的建立研究 果蝇作为一个范例，以解开这种类型的极性在发展和人类疾病。五氯苯酚 通过远程Wnt配体信号协调，导致其受体的不对称定位， 卷曲（Fz）蛋白和相关的信号级联。解释极性需要岩心Fz/PCP系数 并将其中继到相邻小区。所有核心Fz/PCP成员在进化上都是保守的， 规范PCP的所有方面。该Wnt途径不同于典型的Wnt-Fz/β-连环蛋白信号传导（并且正确地表达）。 由相同受体激活的两个Wnt通路之间的信号传导特异性的调节是至关重要的 发展和疾病）。在Wnt-PCP信号传导中，Fz既作为Wnt的受体又作为Wnt的配体。 细胞间结合伴侣货车Gogh/旺（哺乳动物中的Vangl 1/2）。细胞机制影响 极化定位时Fz或旺下游的极性仍然知之甚少。范围 我的实验室的研究和应用的重点是研究长距离的机械相互作用， PCP信号传导和由此产生的细胞生物学读数和细胞内反应。我们最近的重点是 已经/正在发挥旺/Vangl功能，这是由于其与Fz的细胞间相互作用，以及相关的细胞内 反应我们的工作是，也将是由病人派生的数据和各自的功能解剖指导 这些突变。基于令人兴奋的正在进行的实验，我们将解决的生理意义， Fz诱导的旺磷酸化和相关激酶功能，以及这些如何影响旺与 细胞质效应子。这些研究将通过纳入Vangl 1/2相关神经系统疾病的患者数据来辅助。 管路闭合缺陷。与此同时，我们正在解剖细胞内细胞对PCP信号传导的生物学反应 以及这些如何影响定位和与纤毛相关蛋白质的机械相互作用， 在无纤毛的果蝇细胞中能够这样做的优势。结合体内研究和细胞 将进行培养生物化学实验以实现这些目标。五氯苯酚的工艺 建立和Wnt/Fz信号传导与几种医学异常有关， 神经管闭合缺陷和癌症，或一般的纤毛病。获取的信息将促进我们的 了解细胞极化，并在许多疾病背景下提供医学相关性。