The Role of FGF Receptors in Lens Development

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 DESCRIPTION (provided by applicant): Aberrant FGF receptor (FGFR) signaling drives the malignancy of a number of human cancers and also is responsible for a number of human developmental disorders. Likewise, PTEN is a well-known tumor suppressor gene that is inactivated in a large variety of human tumors. FGFRs are receptor tyrosine kinases (RTKs) that activate many cellular responses through a signal transduction pathway that activates both AKT and ERK signaling. Despite their central importance to human health, detailed mechanistic understanding of how Fgfr stimulation dictates diverse cellular responses in different tissues remains incomplete. PTEN is a phosphatase that exhibits activity both on lipids and proteins. Recent literature suggests that FGFR signaling and PTEN signaling genetically interact. The ocular lens is a relatively simple developmental system in which FGFR signaling plays an important role. Inhibition of FGFR activity in vivo leads to lens cell apoptosis and overexpression or exogenous administration of FGF leads to fiber cell differentiation in lens epithelial cells. To dissect the role of FGFR signaling in lens cell survival and differentiation, this application proposes to genetically remove FGFR signaling in the lens both in vivo and in lens explants to decouple survival signals from differentiation signals This proposal will test the hypothesis that PTEN inhibits FGFR- mediated survival without inhibiting FGFR-mediated fiber cell differentiation. In addition to revealing the underlying mechanism by which PTEN regulates FGFR signaling the aims of the proposal will develop the first comparative transcriptome of lens cells with intact and deficient FGFR signaling in differentiating conditions with and without regulation by PTEN.