The long term goal of this project is to understand how a the important family of signaling ligands, 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. In particular we use complex mouse genetics to understand the role of FGF signaling in mesodermal lineages with a special emphasis on extension of the body axis and formation of somites (segmented mesodermal segments that are the building blocks of vertebrate muscle, dermis and vertebral bodies). Our work has made clear that genetic redundancy is an important aspect of this biology;therefore all work in this project emerges from an effort to comprehensively characterize the genetic redundancy of FGF signaling in the mesodermal lineage. Such work is relevant to many cases of cancer where more than one FGF gene may be damaged. To achieve this, we needed to generate and characterized important Cre mouse lines, which are tools that allow the control of gene expression in the early embryo. These include TCre (expressed in the early emerging nascent mesoderm), TCre-Ert2 (activatable in emerging nascent mesoderm at all embryonic stages) and Tbx4-Cre (expressed in a posterior mesodermal domain that includes the allantois, hindlimb, and external genitalia(Dev. Dyn., 2011 in press,). TCre in particular has had a major impact on the field, being essential in about 20 publications, with three published this year(Dev. Biol., 2011 349:395, Dev. Biol., 2011 351:254, (PNAS, 2011 108:4018) and two publications in press. In FY 2011, as part of our general interest in early development, in collaborative studies we have helped to define the role of Pitx2 in extraocular myogenesis (Dev. Biol., 2011 349:395) and Dicer in somitogenesis (Dev. Biol., 2011 351:254). In FY 2011 we also published a major finding that defined which FGF ligands control the differentiation of cells that will form somites (PNAS, 2011 108:4018). In 2005 we had published the surprising insight that Fgf8 not required for this process, although a body of high profile work had placed it in a central position in current models. We showed that Fgf8, together with Fgf4, are required for essential aspects of somitogenesis: expression of oscillating gene domains, WNT pathway genes and markers of undifferentiated presomitic mesoderm. Importantly, we demonstrated the premature differentiation of the entire presomitic mesoderm. By examining similar mutants in which we genetically restored WNT signaling, we demonstrated that FGF signaling operates independently of WNT signaling in this process. This functional redundancy that we uncovered 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. In FY2011, in a collaborative study, we also published (Dev Dyn, in press) the extensive characterization of a mouse line previously generated, but incompletely described, that carries an allele of Tbx4 in which Cre had been knocked in into the genes 3 untranslated region. Most notably, we determined that, despite the requirement for Tbx4 in allantoic vasculogenesis, the presumptive endothelial cells of the allantois do not express Tbx4 and Tbx4-Cre tracing, via activation of Cre reporters, revealed that the umbilical vasculature lineage never expressed Tbx4. These results imply that endothelial lineages are segregated prior to the onset of vasculogenesis, and demonstrate a role for the peri-vascular tissue in vasculogenesis.
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