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

动物如何调节器官大小尚不清楚。最近对果蝇的研究表明， 一种称为“河马”的新信号通路作为器官生长的重要调节器。 对于hippo信号传导途径的组分是突变的细胞表现出以下特征： 过度生长伴随着增殖增加和凋亡减弱。在 在哺乳动物中，已经发现了每个河马途径组分的保守直系同源物。 然而，河马信号在哺乳动物中的作用尚未被探索。这里我们 建议定义河马信号在小鼠乳腺中的作用。鼠标 乳腺是唯一适合于这些研究，因为它经历了乳腺癌诱导 在正常发育和妊娠过程中的增殖和凋亡波。 此外，乳腺是存活的，允许应用 评估河马功能的条件方法。我们已经生成了条件 在几个关键的核心河马途径组件的等位基因，并在分析的过程中， 在乳腺中具有减少的或缺乏hippo信号传导的动物的表型 腺。初步的数据表明，在果蝇中，河马信号发挥了重要作用。 防止过度生长的重要作用。我们将把这些初步观察结果 通过系统性地删除小鼠体内河马信号通路的核心成分， 乳腺和应用一系列的细胞学，细胞为基础的，和分子 定义对HIPPO信令的要求以及定义HIPPO如何 信号传导在分子水平上控制乳腺生长。总之， 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控制机制提供了新的见解 组织中

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.