The long term goal of this project is to understand how a very important family of gene products, called Fibroblast Growth Factors (FGFs), control a wide spectrum of cell biological behaviors such as proliferation, cell death, migration, stem cell maintenance and gene expression. FGFs, when dysregulated, are instrumental in various forms of cancer, and the particular FGFs we study play important roles in breast and prostate cancer. To achieve the project's long terms goals, we focus on the normal role FGFs play during mouse embryogenesis. Therefore our short term goals are to generate the necessary mouse strains that will allow us to control FGF gene expression during embryogenesis and to generate and test specific hypotheses concerning FGF action in the embryo. For example, we recently overturned a hypothesis which stated that FGF8 was required for the process of somitogenesis, the process by which much of the body's muscle, dermis and all vertebrae are generated (Development 132: 3859). This lead to a new hypothesis that the role of FGF8 in this embryonic process was redundant with one or more of the other five FGFs expressed in this region. This issue of redundancy has implications for the biology of cancer as more than one FGF can be acting in a given tumor. Fibroblast growth factors (FGFs) comprise a family of 22 members that govern a wide spectrum of cell biological behaviors such as proliferation, cell death, migration and gene expression. In FY 2009, as part of our general interest in FGF signaling, in collaborative studies we have defined the role of Fgf9 in airway smooth muscle differentiation in lung development (<I>Dev. Dyn.</I>, 2009 238:123). Another family member we have a long standing interest in is <I>Fgf8</I>, which plays an important role in the progression of both breast cancer and prostate cancer. To understand how such abnormal <I>Fgf8</I>expression affects cell function in cancer, our long-term goal is to determine the normal role of <I>Fgf8</I>, during vertebrate embryogenesis, using the mouse as a model system. <I>Fgf8</I>is expressed in a variety of regions of the embryo that may be termed """"""""organizers"""""""": regions that are a source of signals that pattern and thus """"""""organize"""""""" the surrounding tissue. Previously we have generated an allelic series generated at the <I>Fgf8</I>locus (Meyers et al. 1998 <I>Nature Genetics</I>18:136), as well as Cre-mediated tissue-specific knockouts (Lewandoski et al. 2000 <I>Nature Genetics</I>, 26:460;Lewandoski 2001 <I>Nature Reviews Genet.</I>2:743;Lewandoski 2007 <I>Handb Exp Pharmaco</I>178: 235) and revealed a role for <I>Fgf8</I>in organizers that control gastrulation, limb, and brain development. We have produced a valuable mouse line (T-Cre) that expresses Cre specifically throughout all embryonic mesodermal lineages, thus allowing us to control gene expression in these lineages. This line is useful to bypass the embryonic lethal phenotypes of genes that affect early development, yet allows the study of the role of such genes throughout much of the embryo (Verheyden et al, 2005 <I>Development</I>, 132: 4235;Wahl et al, 2007 <I>Development</I>, 134;4033;Dunty et al <I>Development</I>, 135:85;Aulehla, A. et al, 2008 <I>Nat Cell Biol.</I>, 10:186;MacDonald S.T. et al 2008 <I>Cardiovasc Res. </I>, 79: 448;Kumar A, et al, 2008 <I>Dev. Dyn.</I>, 237:5391;Tzchori et al, 2009 <I>Development</I>, 136;1375) . Inactivation of <I>Fgf8</I>with TCre has revealed that <I>Fgf8</I>plays a central role in cell survival and gene expression during kidney development (Perantoni et al 2005, <I>Development</I>, 132: 3859). Another surprising insight emerging from these studies is that <I>Fgf8</I>is not required for several mesodermal signaling centers that control the process of somite formation, where it was thought to play a role. To investigate this, we are studying mutants in which <I>Fgf8</I>and each of the other five <I>Fgfs</I>expressed in these regions are simultaneously inactivated. Importantly, we have uncovered a redundant role between <I>Fgf4</I>and <I>Fgf8</I>in somite formation. This functional redundancy has implications for cancer as both FGFs have been found to be aberrantly active in testicular tumors. Furthermore this redundancy has implications for evolution as the same FGFs play compensatory roles in limb development.
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