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.
This research project employs a model mammalian genetic organism, the mouse, to uncover the genetic control of organ growth and cell proliferation, a process of immediate relevance to human health and disease. Growth is critical for normal development and growth control is defective in cancer cells. Given the conservation of genes and pathways required for most fundamental biological processes in mice and humans, we expect that this project will inform our understanding of growth control and cell proliferation in man and in pathophysiological states, such as cancer.
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