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，称为平面细胞极性（PCP）。细胞极性和有序细胞图案 器官发育和体内平衡取决于 PCP 机制。经典的 PCP 示例包括 果蝇成体角质层结构。同样，在哺乳动物中，五氯苯酚的显着特征在皮肤中很明显， 内耳上皮，或呼吸系统和大多数其他内脏器官。此外，收敛扩展 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 调节许多器官干细胞的不对称细胞分裂。我国PCP建设研究 果蝇是揭示发育和人类疾病中这种极性的范例。五氯苯酚是 由长程 Wnt 配体信号协调，导致其受体的不对称定位， 卷曲 (Fz) 蛋白以及相关的信号级联。需要核心 Fz/PCP 因子来解释极性 在小区内并将其转发到相邻小区。所有核心 Fz/PCP 成员在进化上都是保守的并且 规范 PCP 的所有方面。该 Wnt 通路不同于典型的 Wnt-Fz/β-连环蛋白信号传导（并且正确 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 发育和疾病）。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（哺乳动物中为 Vangl1/2）。影响的细胞机制 极化定位时 Fz 或 Vang 下游的极性仍然知之甚少。范围 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。我们最近的重点是 由于其与 Fz 的细胞间相互作用以及相关的细胞间相互作用，Vang/Vangl 功能一直/正在发挥作用 回复。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 这些突变。基于令人兴奋的正在进行的实验，我们将解决以下问题的生理意义： 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 细胞质效应器。这些研究将通过纳入与 Vangl1/2 相关的神经元患者数据来帮助 管封闭缺陷。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。体内研究和细胞研究的结合 将进行培养生化实验来实现这些目标。 PCP的流程 建立和 Wnt/Fz 信号传导与多种医学异常有关，包括耳聋 to neural tube closure defects and cancer, or ciliopathies in general.获得的信息将推进我们的 了解细胞极化，并提供许多疾病背景下的医学相关性。