The long-term objective of this project is to understand the developmental roles ofthe T-box family of transcription factor genes and how they interact and impinge on signaling pathways during organogenesis. The work started with an exploration ofthe evolution ofthe gene family and the discovery of previously unknown genes in the mammalian genome, eventually defining a family of 17 T-box genes common to mouse and human. A number of these, by virtue of their chromosomal locations, were candidates for human developmental syndromes and our work producing mouse models by targeted mutagenesis validated these predictions. Mutations in human T-box genes were subsequently found to underlie anomalies such as DiGeorge, ulnar-mammary, small patella and Holt-Oram syndromes. There are two main themes to this proposal: to explore how T-box genes interact and to understand how they direct organogenesis through different signaling pathways. To accomplish these goals, we will make use of simple and conditional mutations produced or being produced in our laboratory by targeted mutagenesis as well as mutations from other labs. Several organ systems have been chosen for in-depth Study due to interesting patterns of expression of T-box genes and the relevance of the organ systems to important human diseases: Congenital heart defects are a leading cause of death in humans during the first year of life. At least 4 T-box genes play critical roles in heart development and we will continue to explore these gene mutations individually and in combination to understand how they contribute to normal and abnormal development. Tbx2 and Tbx3 interact during early mammary gland development and are implicated in breast cancers. We will continue to explore these roles using conditional alleles. Interesting expression patterns of T-box genes have been uncovered in the gonads and external genitalia and also in the pancreas during islet development. These lines of investigation will be followed to discover the functional role of these genes and their possible involvement in congenital birth defects in the reproductive system or pancreas development relevant to diabetes, respectively.
Congenital heart defects are the most common birth defects in humans and a leading cause of death in the first year of life. T-box genes are critically involved in heart development and the proposed experiments will unravel the molecular mechanisms underlying normal heart development. In addition, new information on T-box genes in gonad, mammary gland and pancreas development will be forthcoming.
|Lopez-Rivera, Esther; Liu, Yangfan P; Verbitsky, Miguel et al. (2017) Genetic Drivers of Kidney Defects in the DiGeorge Syndrome. N Engl J Med 376:742-754|
|Levin, Heather I; Sullivan-Pyke, Chantae S; Papaioannou, Virginia E et al. (2017) Dynamic maternal and fetal Notch activity and expression in placentation. Placenta 55:5-12|
|Concepcion, Daniel; Washkowitz, Andrew J; DeSantis, Akiko et al. (2017) Cell lineage of timed cohorts of Tbx6-expressing cells in wild-type and Tbx6 mutant embryos. Biol Open 6:1065-1073|
|Borok, Matthew J; Papaioannou, Virginia E; Sussel, Lori (2016) Unique functions of Gata4 in mouse liver induction and heart development. Dev Biol 410:213-222|
|Papaioannou, Virginia E (2016) Concepts of Cell Lineage in Mammalian Embryos. Curr Top Dev Biol 117:185-97|
|Xie, Ting; Liang, Jiurong; Liu, Ningshan et al. (2016) Transcription factor TBX4 regulates myofibroblast accumulation and lung fibrosis. J Clin Invest 126:3626|
|Washkowitz, Andrew J; Schall, Caroline; Zhang, Kun et al. (2015) Mga is essential for the survival of pluripotent cells during peri-implantation development. Development 142:31-40|
|Glaser, Anne; Arora, Ripla; Hoffmann, Sandra et al. (2014) Tbx4 interacts with the short stature homeobox gene Shox2 in limb development. Dev Dyn 243:629-39|
|Leitch, Harry G; Okamura, Daiji; Durcova-Hills, Gabriela et al. (2014) On the fate of primordial germ cells injected into early mouse embryos. Dev Biol 385:155-9|
|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|
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