Cadherin regulation of tissue polarity and growth

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DESCRIPTION (provided by applicant): Epithelial planar cell polarity (PCP) is present when the cells of a tissue are all polarized along a uniform axis lying in the plane of the epithelium. Physiologically important examples of PCP are found in many vertebrate tissues including the respiratory system, where ciliated cells must be polarized in a uniform direction for their beating to drive mucus from the lungs, and the ear, where the sensory hair cells must be polarized in a uniform direction so that their stereocilia are correctly arrayed to respond to sound. Among the most important questions regarding PCP is how individual cells sense the proper direction in which to polarize. Previous studies in Drosophila have provided a partial answer to this question by showing that cells respond to Frizzled, a transmembrane receptor protein, whose activity is present in a gradient across the tissue. However, Frizzled is not itself expressed in a graded fashion and the mechanisms used to establish the Frizzled signaling gradients are poorly understood. In a recent study of PCP in the Drosophila eye, we demonstrated that Fat, a protocadherin protein, is essential for establishing the Frizzled activity gradient that directs PCP. We also showed that Fat is regulated during this process by Dachsous (another protocadherin) and Four-jointed (a transmembrane protein). We further suggested that Fat, Dachsous and Four-jointed may form an evolutionarily conserved signaling cassette that is used to control PCP in many tissues. Fat is also a negative regulator of epithelial cell proliferation. Cells lacking Fat exhibit hyperplasic growth. Despite this critical role, little is known about the Fat regulation or function during growth control. We propose to study the role of Fat by: 1) examining the roles of graded Four-jointed, Dachsous and Fat activity in specifying the direction of PCP, 2) examining the ability of Four-jointed and Dachsous to regulate Fat during the control of cell proliferation, 3) identifying the downstream pathways used by Fat to control PCP and proliferation and 4) determining how Fat is regulated by Four-jointed and Dachsous. These experiments should yield new insights into PCP and growth control as well as into the function of protocadherins, which have been implicated in the Usher Syndrome hearing disorders and as tumor suppressors in liver and colon carcinomas.