Regulation Of Tissue Growth And Morphogenesis By Fat Cadherins

脂肪钙粘蛋白对组织生长和形态发生的调节

• 批准号: 10470309
• 负责人: Jyoti R. Misra
• 金额: $ 39万
• 依托单位: UNIVERSITY OF TEXAS DALLAS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10470309
• 关键词: Address; Affect; Animal Model; Biological Models; Cadherins; Cell Adhesion Molecules; Cell membrane; Cytoplasmic Tail; Defect; Development; Drosophila genus; Endocytosis; Fatty acid glycerol esters; Genes; Growth; Hennekam syndrome; Image; Image Analysis; Malignant Neoplasms; Mediating; Morphogenesis; Mutation; Myosin ATPase; Organ; Pathway interactions; Pattern; Play; Recycling; Regulation; Role; Shapes; Signal Pathway; Signal Transduction; Work; body system; developmental disease; inhibitor; insight; morphogens; mutant; novel; planar cell polarity; quantitative imaging; trafficking

Regulation of Tissue Growth and Morphogenesis by Fat Cadherins Project Summary Formation of optimally functioning organs of appropriate size and shape requires precise coordination of growth and morphogenesis during development. The evolutionarily conserved cell adhesion molecules Dachsous and Fat coordinately regulate tissue growth and patterning by influencing Hippo signaling and planar cell polarity respectively. Mutations in these genes give rise to devastating Van Maldergem and Hennekam syndromes characterized by congenital developmental defects of multiple organ systems. Further, mutations in these genes are also implicated in several cancers. However, there are critical gaps in our understanding of how they regulate growth and morphogenetic processes. We know little about how the spatial organization of the pathway is established and maintained and how the Ds-Fat junctions get coordinately remodeled to allow morphogenesis. Further, we lack a coherent view of how this pathway regulates Hippo signaling. Lastly, it is not clear how Fat regulates organ shape. To address these critical gaps, we will use the fruit fly Drosophila, which provides a robust model system to study this pathway. Our recent work has identified several novel regulators of this pathway and uncovered some intriguing findings, which suggest that vesicular trafficking provides an important layer of regulation in organization of the Fat signaling pathway, an aspect that has been overlooked so far. We will investigate how an intricate interplay between the endocytic machinery and a competitive inhibitor plays a critical role in organization of this pathway. Further, we will investigate how the Ds-Fat junctions get remodeled by endocytosis in a mechanosensitive manner to allow morphogenesis. We have identified a key regulatory motif in the Fat cytoplasmic domain and its interactors, which play an important role in Fat recycling to the plasma membrane. We will characterize how this motif regulates Fat localization at the plasma membrane. Additionally, we will investigate how Fat regulates Hippo signaling through the atypical myosin Dachs. Finally, we will examine how Fat signaling affects the key morphogen gradients and conduct live imaging combined with quantitative image analysis to identify the key cellular rearrangements that mediate organ shape alterations in Fat mutants. These studies will provide novel mechanistic insight into Fat signaling pathway and address several longstanding questions in the field and will help explain the developmental disorders resulting from dysregulation of this pathway.

脂肪钙粘蛋白对组织生长和形态发生的调控 项目摘要 形成具有适当大小和形状的最佳功能器官需要精确的生长协调 以及发育过程中的形态发生。进化上保守的细胞粘附分子Dachsous和 脂肪通过影响Hippo信号传导和平面细胞极性来协调调节组织生长和图案化 分别这些基因的突变引起毁灭性的货车Maldergem和Hennekam综合征 以多器官系统的先天发育缺陷为特征。此外，这些基因的突变 也与几种癌症有关。然而，我们对它们如何监管的理解存在重大差距， 生长和形态发生过程。我们对这条路径的空间组织知之甚少 建立和维持以及DS-脂肪连接如何协调重塑以允许形态发生。 此外，我们缺乏关于该途径如何调节Hippo信号传导的一致观点。最后，不清楚脂肪如何 调节器官形状。为了解决这些关键的差距，我们将使用果蝇果蝇，它提供了一个 强大的模型系统来研究这一途径。我们最近的工作已经确定了几个新的监管机构， 途径，并揭示了一些有趣的发现，这表明囊泡运输提供了一个重要的， 脂肪信号通路组织中的调节层，这是迄今为止被忽视的一个方面。我们 将研究内吞机制和竞争性抑制剂之间复杂的相互作用如何发挥作用， 在这条道路的组织中发挥着重要作用。此外，我们将研究DS-脂肪连接是如何重塑的， 以机械敏感的方式通过内吞作用以允许形态发生。我们已经确定了一个关键的调控基序 在脂肪胞质结构域及其相互作用物中，其在脂肪向血浆的再循环中起重要作用 膜的我们将描述这个基序如何调节脂肪定位在质膜上。此外，本发明还 我们将研究脂肪如何通过非典型肌球蛋白Dachs调节Hippo信号。最后，我们将研究 脂肪信号传导如何影响关键形态梯度，并结合定量 图像分析，以确定关键的细胞重排，介导脂肪突变体的器官形状改变。 这些研究将为脂肪信号通路提供新的机制见解，并解决几个长期存在的问题。 在该领域的问题，并将有助于解释发育障碍所造成的失调，这 通路