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，无处不在的尖端-基底端和第二轴 在上皮平面内，称为平面细胞极性(PCP)。细胞极性与有序细胞图案化 在器官发育和动态平衡过程中，PCP机制起着至关重要的作用。经典的PCP示例包括 果蝇成虫角质层结构。同样，在哺乳动物中，五氯苯酚的显著方面在皮肤中也很明显， 内耳上皮，或呼吸系统和大多数其他内脏。此外，收敛扩张 原肠发育和神经管闭合的过程需要PCP信号，而PCP通路是相连的 对许多器官的干细胞中不对称分裂的调节。在中国建立初级保健计划的研究 果蝇是解开发育和人类疾病中这种两极的范例。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因素来解释极性 并将其传递给相邻的细胞。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。这个Wnt途径不同于典型的Wnt-Fz/β-catenin信号(并且是正确的 由同一受体(S)激活的两条Wnt通路之间的信号特异性调节是至关重要的 对于发展和疾病)。在Wnt-PCP信号传递中，Fz‘s既是Wnts的受体，又是其配体 细胞间结合伙伴(S)梵高/Vang(哺乳动物中的Vangl1/2)。细胞机制(S)影响 极化定位时Fz或Vang下游的极性仍然知之甚少。范围 而我的实验室的研究和这一应用的重点是研究远程的机械相互作用 PCP信号和由此产生的细胞生物读出和细胞内反应。我们最近关注的焦点是 由于Vang/Vangl与Fz的细胞间相互作用，以及相关的细胞 回应。我们的工作现在和将来也将以患者得出的数据和各自的功能解剖为指导 在这些突变中。基于令人兴奋的正在进行的实验，我们将讨论 FZ诱导的Vang磷酸化和相关的激酶功能，以及这些功能如何影响Vang与 细胞质效应器。这些研究将通过纳入与Vangl1/2相关的神经的患者数据来辅助 管子关闭缺陷。同时，我们正在剖析细胞内对PCP信号的生物反应。 以及这些因素如何影响定位以及与纤毛相关蛋白的机械相互作用 能够在无纤毛的果蝇细胞中这样做的优势。体内研究和细胞研究的结合 为了实现这些目标，将进行培养生化实验。五氯苯酚的生产工艺 建立和WNT/FZ信号与几种医学异常有关，包括耳聋 神经管闭合缺陷和癌症，或一般的纤毛疾病。获得的信息将推动我们的 了解细胞极化，并在许多疾病背景下提供医学相关性。