Growth regulation by the Fat signaling pathway

 描述(由申请人提供)：本提案的目标是确定在发育中的组织中如何调节生长和极性，以形成适当大小和形状的器官。我们将研究控制器官大小和形状的两个过程：ds-Fat信号和细胞骨架张力，这两个过程在控制器官大小和形状方面发挥着基本但尚未完全了解的作用。DS-Fat信号的一个显著特征是，它可以受到Dachsous(DS)和Fj梯度的载体和斜率的调节，从而影响不同的下游过程，这些过程控制平面细胞极性(PCP)，并通过调节河马信号来调节生长。这些梯度极化了细胞内的脂肪活动，这可以从脂肪信号成分DACH的极化中看出。对这一途径的表征将为控制细胞行为提供新的见解，以及模式和生长如何在发育过程中联系在一起。也有人提出，机械力可以在调节器官大小和形状方面发挥作用，但发生这种情况的机制尚不清楚。然而，最近的研究，包括我们对Jub蛋白的调控和作用的表征，表明河马信号通路参与了机械力对生长的调节。这里提出的研究将加强分子理解，例如，由形态原梯度提供的模式如何指导器官发生，细胞内和细胞之间的机械力如何调节器官发生，以及这些生化和生物力学过程是如何整合的。第一个目的是提出研究，以确定控制关键脂肪信号成分DACH的积累和极性的分子机制。第二个目标将集中在定义DACH和其他因素影响平面细胞极性的机制，包括张力依赖和张力非依赖过程。第三个目的是研究调节关键的河马途径蛋白激酶疣以控制生长的分子机制，以及影响疣的生长调节过程之间的相互关系。拟议中的研究将提供对控制组织极性和通过河马信号控制生长的机制的更深层次的理解。器官形状对正常器官功能至关重要，人类对ds-Fat信号的特殊要求与Van Maldergem综合征有关。由于发育过程中不适当的生长导致器官大小或形状不正确，可能会导致出生缺陷。控制器官生长也很重要 了解干细胞如何被用来修复或替换受损的器官，这是再生医学的目标。此外，无法限制成熟生物体的生长会导致癌症。许多器官的癌症都与河马信号失活有关，包括肝、肾、皮肤、脑、肠、肺、卵巢、乳腺和前列腺癌。了解河马信号的调节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.