The objectives of this research are to understand the genetic control of mesoderm specification at gastrulation and to determine how decisions are made at critical junctures between alternative developmental pathways. The hypotheses are 1) that members of the Tbox transcription factor gene family in particular Tbx6 are essential for mesoderm specification and differentiation and 2) that there may be additional members of the Tbx6 subfamily also involved. These hypotheses are based in large part on the null mutation we have produced in Tbx6 and on phylogenetic and mutational studies in other species. The Tbx6 mutation affects the differentiation of mesoderm destined to form the somites and eventually the bulk of the musculoskeletal system. In mutants there is a dramatic switch in the differentiation pathway of posterior mesoderrn to a neural pathway resulting in embryos with three parallel neural tubes and no posterior somites. For all of these studies the mouse will be used as a model system because of its similarity to the human and because of the availability of genetic resources. Understanding the factors that control the development of the musculoskeletal system has important health relatedness for understanding congenital anomalies and chronic diseases of muscles and bone.
Specific Aim 1. To determine the lineage of all Tbx6expressing cells in order to characterize fully the phenotypic results of a null mutation in Tbx6 and to examine the developmental potential of Tbx6 null cells.
Specific Aim 2. To explore the mechanism of action of Tbx6 in the specification of mesoderm during gastrulation using a Cremediated transgenic approach for misexpression of Tbx6.
Specific Aim 3. To produce a new Tbx6 mutant allele coding for a truncated protein with only the DNA binding domain and no transcriptional regulatory domain.
Specific Aim 4. To isolate and characterize additional members of the Tbx6 subfamily in the mouse with special emphasis on isolating the orthologs of genes known in other species to play a role in mesoderm development.
|Hadjantonakis, Anna-Katerina; Pisano, Elinor; Papaioannou, Virginia E (2008) Tbx6 regulates left/right patterning in mouse embryos through effects on nodal cilia and perinodal signaling. PLoS One 3:e2511|
|Passamaneck, Yale J; Di Gregorio, Anna; Papaioannou, Virginia E et al. (2006) Live imaging of fluorescent proteins in chordate embryos: from ascidians to mice. Microsc Res Tech 69:160-7|
|Plusa, Berenika; Frankenberg, Stephen; Chalmers, Andrew et al. (2005) Downregulation of Par3 and aPKC function directs cells towards the ICM in the preimplantation mouse embryo. J Cell Sci 118:505-15|
|Eakin, Guy S; Hadjantonakis, Anna-Katerina; Papaioannou, Virginia E et al. (2005) Developmental potential and behavior of tetraploid cells in the mouse embryo. Dev Biol 288:150-9|
|Hadjantonakis, Anna-Katerina; Papaioannou, Virginia E (2004) Dynamic in vivo imaging and cell tracking using a histone fluorescent protein fusion in mice. BMC Biotechnol 4:33|
|Chapman, Deborah L; Cooper-Morgan, Amalene; Harrelson, Zachary et al. (2003) Critical role for Tbx6 in mesoderm specification in the mouse embryo. Mech Dev 120:837-47|
|Hadjantonakis, Anna-Katerina; Papaioannou, Virginia E (2002) Can mammalian cloning combined with embryonic stem cell technologies be used to treat human diseases? Genome Biol 3:REVIEWS1023|
|Watabe-Rudolph, Masami; Schlautmann, Nicole; Papaioannou, Virginia E et al. (2002) The mouse rib-vertebrae mutation is a hypomorphic Tbx6 allele. Mech Dev 119:251-6|
|Hadjantonakis, A; Papaioannou, V (2001) The stem cells of early embryos. Differentiation 68:159-66|