We are studying the molecular mechanisms that are involved in the induction and patterning of the early heart tube. To begin to identify the molecular pathways involved in heart development, we are studying the endogenous role of genes implicated in human congenital heart disease, the most common form of heart disease in childhood occurring in about 1% of live births and up to 10% of stillbirths. Despite the high incident of congenital heart disease only in a few instances has the genetic basis for any one type of disease been identified. Recently, it has been shown that patients with the Noonan syndrome often have mis-sense mutations in the Shp-2/SH-PTP2 gene. Shp-2/SH-PTP2 encodes for a nonreceptor phosphatase required for FGF/MAPK signaling. A second example is the Holt-Oram syndrome (HOS), a disease associated with mutations in the coding region of the transcription factor TBX5. Several of the clinical features of Noonan syndrome and HOS can overlap. For example, patients with either syndrome often display atrial septal defects suggesting that the two proteins may function in a similar pathway. Consistent with this hypothesis, we have shown a direct link between the FGF/MAPK signal transduction pathway and TBX5 transcriptional activity. We have also shown that TBX5 is post-translationally modified through phosphorylation, and that mutation of an evolutionarily conserved FGF/MAPK site results in alterations of TBX5 function. To test the hypothesis that FGF/MAPK/SH-PTP2 pathway is critical to Tbx5 activity and heart development in vivo, we plan to determine the cellular and molecular relationship between the FGF/MAPK/SH-PTP2 and Tbx5.
The specific aims of this proposal are: to establish the molecular and cellular relationship between FGF/MAP kinase signaling pathway and Tbx5 in heart development, determine the role for SH-PTP2 with respect to TBX5 activity and early heart development, to identify and characterize the role of FGF/MAP/SH-PTP2 in TBX5 post-translational modifications.
| Langdon, Yvette; Tandon, Panna; Paden, Erika et al. (2012) SHP-2 acts via ROCK to regulate the cardiac actin cytoskeleton. Development 139:948-57 |
| Christine, Kathleen S; Conlon, Frank L (2008) Vertebrate CASTOR is required for differentiation of cardiac precursor cells at the ventral midline. Dev Cell 14:616-23 |
| Langdon, Yvette G; Goetz, Sarah C; Berg, Anna E et al. (2007) SHP-2 is required for the maintenance of cardiac progenitors. Development 134:4119-30 |
| Goetz, Sarah C; Conlon, Frank L (2007) Cardiac progenitors and the embryonic cell cycle. Cell Cycle 6:1974-81 |
| Brown, Daniel D; Christine, Kathleen S; Showell, Christopher et al. (2007) Small heat shock protein Hsp27 is required for proper heart tube formation. Genesis 45:667-78 |
| Showell, Chris; Christine, Kathleen S; Mandel, Elizabeth M et al. (2006) Developmental expression patterns of Tbx1, Tbx2, Tbx5, and Tbx20 in Xenopus tropicalis. Dev Dyn 235:1623-30 |
| Chen, Jian-Fu; Mandel, Elizabeth M; Thomson, J Michael et al. (2006) The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet 38:228-33 |
| Goetz, Sarah C; Brown, Daniel D; Conlon, Frank L (2006) TBX5 is required for embryonic cardiac cell cycle progression. Development 133:2575-84 |
| Brown, Daniel D; Davis, Anna C; Conlon, Frank L (2006) Xtn3 is a developmentally expressed cardiac and skeletal muscle-specific novex-3 titin isoform. Gene Expr Patterns 6:913-8 |
| Brown, Daniel D; Martz, Shauna N; Binder, Olav et al. (2005) Tbx5 and Tbx20 act synergistically to control vertebrate heart morphogenesis. Development 132:553-63 |
Showing the most recent 10 out of 12 publications
