verbatim): The molecular mechanisms by which congenital heart malformations arise are largely unknown. One of the few genes associated with developmental cardiac anomalies in humans is TBX5. Mutations in the TBX5 have been identified in families with Holt-Oram Syndrome (HOS) which includes atrial septal defects and other cardiac anomalies. The association of TBX5 with HOS provides a unique opportunity to examine the causes of congenital heart malformations at the molecular level. Tbx5 is a member of the T-box family of transcription factors and is expressed in a pattern consistent with roles in atrial lineage determination and cardiomyocyte cell proliferation. The central hypothesis is that Tbx5 promotes atrial lineage determination and inhibits cardiomyocyte proliferation. TBX5 mutations associated with HOS in the human population can result in expression of mutant proteins. The proposed experiments will examine the regulatory functions of HOS mutant proteins (HOSTbx5) relative to Tbx5 in atrial lineage determination and cardiomyocyte proliferation. Mechanistic experiments will be performed in both chicken and mouse embryos taking advantage of the strengths of each system. Chicken embryo heart segment specific explants will be used to determine how Tbx5 regulates atrial lineage determination and cardiomyocyte cell proliferation at cellular and molecular levels. Transgenic mice will be used to determine the effects of targeted alterations in Tbx5 function on heart morphogenesis in vivo.
The specific aims are: 1) Target expression of Tbx5 or HOSThx5 to distinct segments of the heart forming region during atrial lineage determination. 2) Quantify cardiomyocyte proliferation in the presence of Thx5 or HOSTbx5. 3) Identify potential downstream targets of Tbx5 using a candidate gene approach. 4) Target heart compartment-specific expression of Tbx5 or HOSTbx5 in transgenic mice during early chamber morphogenesis. Together these studies will provide a thorough determination of Tbx5 function at molecular, cellular and organogenic levels. The functional comparison of Tbx5 with HOSTbx5 throughout the study will provide insight into potential molecular determinants of congenital heart disease. The long term goal of the proposed studies is to identify specific molecular and cellular mechanisms by which alterations in Tbx5 function evolve into congenital heart disease.
| Yutzey, Katherine E; Robbins, Jeffrey (2007) Principles of genetic murine models for cardiac disease. Circulation 115:792-9 |
| Clark, Krista L; Yutzey, Katherine E; Benson, D Woodrow (2006) Transcription factors and congenital heart defects. Annu Rev Physiol 68:97-121 |
| Plageman Jr, Timothy F; Yutzey, Katherine E (2005) T-box genes and heart development: putting the ""T"" in heart. Dev Dyn 232:11-20 |
| Plageman Jr, Timothy F; Yutzey, Katherine E (2004) Differential expression and function of Tbx5 and Tbx20 in cardiac development. J Biol Chem 279:19026-34 |
| Lincoln, Joy; Alfieri, Christina M; Yutzey, Katherine E (2004) Development of heart valve leaflets and supporting apparatus in chicken and mouse embryos. Dev Dyn 230:239-50 |
