Growth regulation by the Fat signaling pathway

 描述（由申请人提供）：本提案的目标是确定如何在发育组织中调节生长和极性，以形成适当大小和形状的器官。我们将研究在控制器官大小和形状方面发挥基本但不完全理解的作用的两个过程：Ds-Fat信号传导和细胞骨架张力。Ds-Fat信号传导的一个显着特征是，它可以通过Dachsous（Ds）和Four-jointed（Fj）梯度的矢量和斜率进行调节，以影响控制平面细胞极性（PCP）的不同下游过程，并通过调节Hippo信号传导，生长。这些梯度抑制了细胞内的脂肪活性，这可以通过脂肪信号成分Dachs的极化来观察。这一途径的表征将为细胞行为的控制提供新的见解，以及在发育过程中如何将模式化和生长联系起来。也有人提出，机械力可以在调节器官大小和形状中发挥作用，但这种情况发生的机制还不清楚。然而，最近的研究，包括我们对Jub蛋白的调节和作用的表征，已经暗示了Hippo信号通路通过机械力调节生长。 这里提出的研究将提高分子的理解如何图案化，例如由形态梯度提供，指导器官发生，细胞内和细胞之间的机械力如何调节器官发生，以及这些生物化学和生物力学过程是如何整合的。第一个目标是研究确定控制关键脂肪信号成分Dachs的积累和极性的分子机制。第二个目标将集中于定义Dachs和其他因素影响平面细胞极性的机制，包括张力依赖性和张力无关性过程。第三个目标是研究调节关键Hippo途径激酶Warts以控制生长的分子机制，以及影响Warts的生长调节过程之间的相互关系。 拟议的研究将提供对控制组织极性的机制的更深入的理解，以及通过Hippo信号控制生长的机制。器官形状对于正常的器官功能是至关重要的，并且通过其与货车Maldergem综合征的关联已经揭示了人类对Ds-Fat信号传导的特定要求。由于发育过程中的不适当生长导致器官大小或形状不正确，可能导致出生缺陷。控制器官生长也很重要 了解干细胞如何用于修复或替换受损器官，这是再生医学的目标。此外，无法限制成熟生物体的生长导致癌症。各种器官中的癌症都与Hippo信号的失活有关，包括肝脏，肾脏，皮肤，大脑，肠，肺，卵巢，乳腺和前列腺了解Hippo信号的调节因此与一系列人类健康问题有关，包括出生缺陷，癌症和再生医学。

 DESCRIPTION (provided by applicant): The goal of this proposal is to determine how growth and polarity are regulated in developing tissues to form organs of appropriate size and shape. We will investigate two processes that play fundamental yet incompletely understood roles in controlling organ size and shape: Ds-Fat signaling and cytoskeletal tension. A remarkable feature of Ds-Fat signaling is that it can be regulated by the vector and slope of Dachsous (Ds) and Four-jointed (Fj) gradients to influence distinct downstream processes that control planar cell polarity (PCP) and, through regulation of Hippo signaling, growth. These gradients polarize Fat activity within cells, as can be visualized by the polarization of the Fat signaling component Dachs. Characterization of this pathway will provide novel insights into the control of cell behavior, and how patterning and growth can be linked during development. It has also been proposed that mechanical forces could play roles in modulating organ size and shape, but the mechanisms by which this occurs are not well understood. Recent studies however, including our characterization of the regulation and role of the Jub protein, have implicated the Hippo signaling pathway in regulation of growth by mechanical forces. The studies proposed here will enhance molecular understanding of how patterning, e.g. as provided by morphogen gradients, directs organogenesis, how mechanical forces within and between cells modulate organogenesis, and how these biochemical and biomechanical processes are integrated. The first aim proposes studies to define molecular mechanisms that control the accumulation and polarity of the key Fat signaling component Dachs. The second aim will focus on defining mechanisms by which Dachs and other factors influence planar cell polarity, including both tension-dependent and tension-independent processes. The third aim investigates molecular mechanisms that regulate the key Hippo pathway kinase Warts to control growth, and interrelationships among growth-regulatory processes that affect Warts. The proposed studies will provide a deeper understanding of mechanisms that control tissue polarity, and that control growth through Hippo signaling. Organ shape is crucial for normal organ function, and specific requirements for Ds-Fat signaling in humans have been revealed by its association with Van Maldergem syndrome. As inappropriate growth during development results in organs that are incorrectly sized or shaped, it can cause birth defects. Controlling organ growth is also important for understanding how stem cells can be used to repair or replace damaged organs, which is a goal of regenerative medicine. Additionally, the inability to limit growth in mature organisms results in cancer. Cancers in a wide variety of organs have been associated with inactivation of Hippo signaling, including liver, kidney, skin, brain, intestine, lung, ovary, breast, and prostate Understanding the regulation of Hippo signaling is thus relevant to a range of human health issues, including birth defects, cancer, and regenerative medicine.