Functional Analysis of Cilia in Hedgehog Signaling and Gli Activity Regulation

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Hedgehog (Hh) family of secreted proteins is critical for cell proliferation and cell fate determination in animal development. The PI recently showed cilia, tiny 'hairs' on top of most mammalian cells, are needed for cells to respond to Hh. In this proposal, the PI will investigate whether and how cilia influence the ability of Gli proteins, a group of three proteins involved in gene expression regulation, to mediate the cell's response to Hh. First, the PI will genetically test the hypothesis that cilia are essential for the activation of all three Gli proteins. Subsequently, the PI will investigate the mechanisms by which these Gli proteins are transported into the cilia, using cell biological and biochemical approaches. Finally, the PI will test the hypothesis that Gli proteins cannot be activated without getting into cilia by genetically engineering Gli proteins such that they are no longer transported into the cilia. The research program proposed here will not only elucidate the mechanism by which cilia regulate the activities of Gli proteins, but also provide more general insight into how basic cellular machinery regulates information flow to ensure normal development of an animal. The integration of research and education will be achieved by applying the research material to undergraduate teaching, encouraging undergraduate students to participate in lab research and providing opportunities for graduate students to be involved in teaching activities. Female and minority students will be recruited to participate in this project through NASA sponsored programs. Finally, the PI will be actively involved in outreach activities such as hosting high school students and participating in lecture series aimed at disseminating scientific knowledge to the local community.