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: 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
• 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

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.

上皮细胞在两个轴上极化其功能，无处不在的顶碱极性和第二轴 在上皮平面中，称为平面细胞极性（PCP）。细胞极性和有序的细胞模式 在器官发育和体内稳态过程中，取决于PCP机制。经典的PCP示例包括 果蝇成人可爱的结构。同样，在哺乳动物中，PCP的醒目方面是皮肤中的证据， 内耳上皮或呼吸系统和大多数其他内部器官。此外，收敛扩展 口水和神经管闭合期间的过程需要PCP信号，并且PCP途径链接 调节许多器官干细胞中的不对称细胞分裂。 PCP建立的研究 果蝇是开发和人类疾病中这种极性的范式。 PCP是 由远程Wnt配体信号协调，导致其接收器的不对称定位， 卷曲（FZ）蛋白质和相关的信号级联。核心FZ/PCP因素需要解释极性 在细胞内，并将其传递到相邻的细胞中。所有核心FZ/PCP成员都是进化构成的，并且 调节所有PCP方面。该Wnt-pathway与规范的Wnt-FZ/β-catenin信号传导不同（并正确 由同一受体激活的两个Wnt-pathways之间信号传导特异性的调节是关键的 在Wnt-PCP信号的FZ行为中，作为Wnt和配体的受体 细胞间结合伴侣van gogh/vang（哺乳动物中的vangl1/2）。影响的细胞机制 两极分化定位时FZ或Vang的极性仍然非常了解。范围 我的实验室研究的重点是研究远程的机械相互作用 PCP信号传导以及所得的细胞生物学读出和细胞内反应。我们最近的重点是 由于其与Fz的细胞间相互作用，IS/IS在Vang/Vangl函数上 回复。我们的工作是并且将由患者衍生的数据和相对功能解剖所指导 这些突变。基于令人兴奋的正在进行的实验，我们将解决 FZ诱导的Vang磷酸化和相关的激酶功能，以及这些如何影响Vang的相互作用 细胞质作用。这些研究将通过包括vangl1/2相关的中性的患者数据来帮助 管闭合缺陷。同时，我们正在解剖细胞内细胞生物学对PCP信号的反应 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，与 能够在非纤毛果蝇细胞中这样做的优点。体内研究和细胞的结合 将进行培养生化实验以实现这些目标。 PCP的过程 建立和WNT/FZ信号已与几种医学异常有关，从耳聋 神经管闭合缺陷和癌症，或一般的纤毛病。获得的信息将推动我们的 了解细胞极化，并在许多疾病情况下提供医学相关性。