The developing mesoderm of the vertebrate embryo is subdivided into four populations each giving rise to different tissues and organs; the paraxial mesoderm gives rise to the somites. The transcription factor, Tbx6, is absolutely required for the development of the posterior paraxial mesoderm: in Tbx6 mutants the posterior somites are replaced by ectopic neural tubes. The primary aim of this project is to provide a more detailed picture of the molecular mechanisms operating in the formation of paraxial mesoderm and will use the Tbx6 gene as the primary tool to uncover the factors directing paraxial mesoderm formation and specification.
The specific aims are: (I) To use transgenics and comparative genomics to identify and characterize the cis-regulatory regions directing Tbx6 expression during embryogenesis. (II) To test the ability of candidate transcription factors to bind to the regulatory regions of Tbx6. The prime candidates are LEF-1/TCF1, which function through the secreted signaling molecule Wnt-3a, and RBP-JK, which functions in the Notch signaling pathway. (Ill) To identify the DNA binding site of Thx6 and to test the ability of Tbx6 to bind to the regulatory regions of candidate downstream targets. (IV) To develop a fate map of Tbx6 expressing cells in both normal and mutant backgrounds. These studies will not only help us to understand the function of Thx6 in anterior somite formation but also the fate of Tbx6 expressing cells in various mutant backgrounds, including T. The somites are crucial components of the vertebrate body plan but a fuller understanding of the molecular events required for their development will be of more than mere academic interest. Such knowledge may provide insight into the cause of different types of birth defects and in the future may greatly assist attempts to direct the development of stem cells to produce specific types of tissues for transplants.
| Chapman, Deborah L (2018) Impaired intermediate formation in mouse embryos expressing reduced levels of Tbx6. Genesis :e23270 |
| White, Phillip H; Chapman, Deborah L (2005) Dll1 is a downstream target of Tbx6 in the paraxial mesoderm. Genesis 42:193-202 |
| White, Phillip H; Farkas, Deborah R; Chapman, Deborah L (2005) Regulation of Tbx6 expression by Notch signaling. Genesis 42:61-70 |
| White, Phillip H; Farkas, Deborah R; McFadden, Erin E et al. (2003) Defective somite patterning in mouse embryos with reduced levels of Tbx6. Development 130:1681-90 |
