Congenital heart and limb malformations in newborns can lead to devastating losses of body function, resulting in poor quality of life or even death. Thus, the detrimental impact on the affected individuals, families, and society emphasize the need for a better understanding of the underlying mechanisms that control and regulate the respective developmental pathways. Among the various players in those mechanisms, T-box transcription factors appear to have key roles. In particular, the T-box gene Tbx5 reveals a unique expression pattern in developing upper limbs and the heart. Direct evidence for a role in controlling limb and heart pattern comes from mutations in TBX5 in humans and mouse embryos lacking Tbx5. A reduced level of Tbx5 protein causes Holt-Oram syndrome (HOS), a disease characterized by developmental defects of the upper limbs and heart septation. Major cardiac and limb malformations in infants of mothers with environmentally induced type 2 diabetes are reminiscent to those seen in HOS. These striking similarities suggest a relationship between dietary factors and Tbx5 gene function. Our laboratory has identified a novel molecular scaffolding protein that binds Tbx5 and may be the molecular link between insulin signaling and Tbx5 activity in the heart and limb. In spite of its importance in development and disease, the mechanisms by which the Tbx5 protein exerts its functions are not yet understood. The long-term objective of this project is to elucidate how Tbx transcription factors interact in a molecular regulatory network in a developmentally controlled manner, and how and why these processes sometimes fail.
We aim i n this study to characterize the relationship of Tbx5 with insulin signaling, and thereby investigate a potential environmental role in developmental defects. We will utilize molecular biology, cell biology, and biochemistry to determine the expression, localization, and interactions of the novel protein LMP-4 with Tbx5 and the insulin receptor. Ultimately, these studies will provide a more in-depth view of Tbx5 function, lead to a better understanding of cardiac birth defects associated with diabetes and disturbed glucose and insulin metabolism, and will provide insight into a previously unknown mechanism for transcription factor regulation in development.
|Isphording, D; Leylek, A M; Yeung, J et al. (2004) T-box genes and congenital heart/limb malformations. Clin Genet 66:253-64|
|Krause, Ange; Zacharias, William; Camarata, Troy et al. (2004) Tbx5 and Tbx4 transcription factors interact with a new chicken PDZ-LIM protein in limb and heart development. Dev Biol 273:106-20|