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 2010, 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 (Dev. Dyn., 2009 238:123). Another family member we have a long standing interest in is Fgf8, which plays an important role in the progression of both breast cancer and prostate cancer. To understand how such abnormal Fgf8 expression affects cell function in cancer, our long-term goal is to determine the normal role of Fgf8, during vertebrate embryogenesis, using the mouse as a model system. Fgf8 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 Fgf8 locus (Meyers et al. 1998 Nature Genetics 18:136), as well as Cre-mediated tissue-specific knockouts (Lewandoski et al. 2000 Nature Genetics, 26:460;Lewandoski 2001 Nature Reviews Genet. 2:743;Lewandoski 2007 Handb Exp Pharmaco 178: 235) and revealed a role for Fgf8 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 Development, 132: 4235;Wahl et al, 2007 Development, 134;4033;Dunty et al Development, 135:85;Aulehla, A. et al, 2008 Nat Cell Biol., 10:186;MacDonald S.T. et al 2008 Cardiovasc Res. , 79: 448;Kumar A, et al, 2008 Dev. Dyn., 237:5391;Tzchori et al, 2009 Development, 136;1375) . Inactivation of Fgf8 with TCre has revealed that Fgf8 plays a central role in cell survival and gene expression during kidney development (Perantoni et al 2005, Development, 132: 3859). Another surprising insight emerging from these studies is that Fgf8 is not required in an important signaling center that controls the process of somite formation, where it was thought to play a role. To investigate this, we are studying mutants in which Fgf8 and each of the other five Fgfs expressed in these regions are simultaneously inactivated. Importantly, we have uncovered several redundant roles between Fgf4 and Fgf8 in somite formation and differentiation. One exciting insight is that both genes cooperate to keep presomitic tissue undifferentiated. 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. We have also undertaken an extensive investigation into the role of the Fgf3 singly, and in combination with other Fgfs. We have discovered that Fgf3 acts as a key cell survival factor in the presomtic tissue.
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