Genetic Analysis of the Hippo Signaling Pathway in the Mouse Mammary Gland

动物是如何调节器官大小的还不得而知。最近对果蝇的研究指向 一个新的信号通路被称为“河马”，作为器官生长的重要调节因素。 河马信号通路组件的突变细胞表现出以下特征 细胞过度生长伴随细胞增殖增加，细胞凋亡减弱。在……里面 哺乳动物中，已经发现了河马途径每个组成部分的保守同源基因。 然而，河马信号在哺乳动物中的作用还没有被探索过。在这里我们 建议定义河马信号在小鼠乳腺中的作用。鼠标 乳腺特别适合于这些研究，因为它经历了荷尔蒙诱导 正常发育和妊娠过程中的增殖和凋亡波。 此外，乳腺对于生存能力是可有可无的，允许应用 评价河马功能的条件方法。我们已经生成了有条件的 几个关键核心河马途径组件上的等位基因，正在分析过程中 乳腺中河马信号减弱或缺失的动物的表型 腺体。初步数据表明，就像在果蝇中一样，河马信号在 在防止过度生长方面发挥重要作用。我们将延长这些初步观察结果 通过系统地删除小鼠河马信号通路的核心组件 通过应用一系列细胞学、细胞学、细胞学和分子生物学方法 方法来定义对河马信令的要求以及定义河马如何 信号转导在分子水平上控制乳腺生长。总而言之， 拟议的研究将确定河马信号在正常乳腺中的功能 从而为哺乳动物器官大小的控制机制提供了新的见解 纸巾。

How animals regulate organ size is unknown. Recent studies in Drosophila point towards a novel signaling pathway called “hippo” as an important regulator of organ growth. Cells that are mutant for components of the hippo signaling pathway exhibit features of overgrowth accompanied by increased proliferation and attenuated apoptosis. In mammals, conserved orthologs of each hippo pathway component have been found. However, the role of hippo signaling in mammals has not been explored. Here we propose to define the role of hippo signaling in the mouse mammary gland. The mouse mammary gland is uniquely suited for these studies as it undergoes hormone-induced waves of proliferation and apoptosis during normal development and pregnancy. Moreover, the mammary gland is dispensable for viability, allowing application of conditional approaches for assessment of hippo function. We have generated conditional alleles at several key core hippo pathway components and are in the process of analyzing the phenotype of animals that have reduced or absent hippo signaling in the mammary gland. Preliminary data suggests that as in Drosophila, hippo signaling plays an important role in preventing overgrowth. We will extend these preliminary observations by systematically deleting core components of the hippo signaling pathway in the mouse mammary gland and by applying a series of cytological, cell-based, and molecular methods to define both the requirement for hippo signaling and to define how hippo signaling controls mammary gland growth on a molecular level. In summary, the proposed research will define functions for hippo signaling in the normal mammary gland and thus provide novel insight into mechanism of organ size control in mammalian tissues.