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. Increased expression of specific members of this family, such as Fgf8, play 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. Recently 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., in press) . 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 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 Fgf8 and each of the other five Fgfs expressed in these regions are simultaneously inactivated. Importantly, we have uncovered a redundant role between Fgf4 and Fgf8 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. One of the intriguing insights that has emerged from these studies is that at different stages of embryogenesis FGF signaling plays different roles in cell migration, proliferation, patterning, and survival. How is this diversity of response achieved? To answer this question, we are studying downstream targets of FGF signaling. One set of such target genes is the homeobox genes Gbx1 and 2. The role of the mouse Gbx2 gene during neurulation and particularly in defining the mid/hindbrain organizer has been well documented. We have extended this analysis by studying a hypomorphic (partial-loss-of-function) Gbx2 allele, which has revealed that Gbx2 is required at certain threshold levels for different parts of the brain (Waters and Lewandoski 2006 Development, 133: 1991). Compared to Gbx2 relatively little has been reported about Gbx1. We recently described the cloning and embryonic expression pattern of Gbx1 and defined regions of potential molecular redundancy with Gbx2. (Waters et al 2003 Gene Exp. Patterns. 3:313). We are currently studying mice with an allelic series at the Gbx1 locus to study it's function during development, including its role in FGF signaling and its interactions with Gbx2.
| Jacques, Bonnie E; Montcouquiol, Mireille E; Layman, Erynn M et al. (2007) Fgf8 induces pillar cell fate and regulates cellular patterning in the mammalian cochlea. Development 134:3021-9 |
| Lewandoski, M (2007) Analysis of mouse development with conditional mutagenesis. Handb Exp Pharmacol :235-62 |
| Waters, Samuel T; Lewandoski, Mark (2006) A threshold requirement for Gbx2 levels in hindbrain development. Development 133:1991-2000 |
| Perantoni, Alan O; Timofeeva, Olga; Naillat, Florence et al. (2005) Inactivation of FGF8 in early mesoderm reveals an essential role in kidney development. Development 132:3859-71 |
| Waters, Samuel T; Wilson, Catherine P; Lewandoski, Mark (2003) Cloning and embryonic expression analysis of the mouse Gbx1 gene. Gene Expr Patterns 3:313-7 |
