The long-term goal of the proposed research is to understand the complex genetic control of determination of left/right (L/R) body axis in the mammalian embryo. Specification of the L/R axis sets up a developmental cascade that coordinates development of the viscera and is essential for the correct placement and alignment of organ systems and vasculature. Defective L/R patterning can lead to congenital cardiac malformations, vascular anomalies and other serious health issues. We will investigate the roles of two T-box transcription factor genes, Brachyury (T) and Tbx6. T has previously been shown to affect laterality in mice although the phenotype has not been fully explored. Tbx6 had not previously been implicated in laterality determination, but our preliminary studies and published work reveals heterotaxia in mutants, indicating an important role for this gene, and shows effects on Notch signaling and cilia within the node. We will investigate these genes to determine the nature and mechanism of the defects. Understanding how these genes impinge on this basic developmental process will add to understanding of the genetic and morphological landscape within w hich the L/R body axis is determined.
Specific Aim 1. To determine the nature and mechanisms of the laterality defects associated with Brachyury (T) mutation in the mouse and place T and Tbx6 in the genetic hierarchy of genes affecting L/R determination.
Specific Aim 2. To examine the structure and function of the node and nodal cilia in Tbx6 and T mutant embryos at the time of L/R axis determination.
Specific Aim 3. To determine the lineage of cells of the node with respect to their prior expression of Tbx6.
Situs inversus, the complete reversal of the left/right body axis is compatible with a normal life expectancy. However, heterotaxia, the random disruption of situs of different organs, can result in serious health problems, for example the lack or duplication of organs, such as spleen, or cardiac and vascular anomalies. This study will lead to a greater understanding of the basic biological processes that lead to the disruption of axis determination, an important developmental process.
| Concepcion, Daniel; Papaioannou, Virginia E (2014) Nature and extent of left/right axis defects in T(Wis) /T(Wis) mutant mouse embryos. Dev Dyn 243:1046-53 |
| Nowotschin, Sonja; Ferrer-Vaquer, Anna; Concepcion, Daniel et al. (2012) Interaction of Wnt3a, Msgn1 and Tbx6 in neural versus paraxial mesoderm lineage commitment and paraxial mesoderm differentiation in the mouse embryo. Dev Biol 367:1-14 |
| Takemoto, Tatsuya; Uchikawa, Masanori; Yoshida, Megumi et al. (2011) Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature 470:394-8 |
