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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010338-12
Application #
8348982
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2011
Total Cost
$402,972
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Morales, Aixa V; Espeso-Gil, Sergio; OcaƱa, Inmaculada et al. (2016) FGF signaling enhances a sonic hedgehog negative feedback loop at the initiation of spinal cord ventral patterning. Dev Neurobiol 76:956-71
Hung, Irene H; Schoenwolf, Gary C; Lewandoski, Mark et al. (2016) A combined series of Fgf9 and Fgf18 mutant alleles identifies unique and redundant roles in skeletal development. Dev Biol 411:72-84
Anderson, Matthew J; Schimmang, Thomas; Lewandoski, Mark (2016) An FGF3-BMP Signaling Axis Regulates Caudal Neural Tube Closure, Neural Crest Specification and Anterior-Posterior Axis Extension. PLoS Genet 12:e1006018
Anderson, Matthew J; Southon, Eileen; Tessarollo, Lino et al. (2015) Fgf3-Fgf4-cis: A new mouse line for studying Fgf functions during mouse development. Genesis :
Cunningham, Thomas J; Brade, Thomas; Sandell, Lisa L et al. (2015) Retinoic Acid Activity in Undifferentiated Neural Progenitors Is Sufficient to Fulfill Its Role in Restricting Fgf8 Expression for Somitogenesis. PLoS One 10:e0137894
Yun, Kangsun; Ajima, Rieko; Sharma, Nirmala et al. (2014) Non-canonical Wnt5a/Ror2 signaling regulates kidney morphogenesis by controlling intermediate mesoderm extension. Hum Mol Genet 23:6807-14
Anderson, Matthew J; Naiche, L A; Wilson, Catherine P et al. (2013) TCreERT2, a transgenic mouse line for temporal control of Cre-mediated recombination in lineages emerging from the primitive streak or tail bud. PLoS One 8:e62479
Sauer, Stephan; Burkett, Sandra S; Lewandoski, Mark et al. (2013) A CO-FISH assay to assess sister chromatid segregation patterns in mitosis of mouse embryonic stem cells. Chromosome Res 21:311-28
Williams, Margot; Burdsal, Carol; Periasamy, Ammasi et al. (2012) Mouse primitive streak forms in situ by initiation of epithelial to mesenchymal transition without migration of a cell population. Dev Dyn 241:270-83
Naiche, L A; Holder, Nakisha; Lewandoski, Mark (2011) FGF4 and FGF8 comprise the wavefront activity that controls somitogenesis. Proc Natl Acad Sci U S A 108:4018-23

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