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.

Public Health Relevance

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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Coulombe, James N
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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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
Papaioannou, Virginia E (2014) The T-box gene family: emerging roles in development, stem cells and cancer. Development 141:3819-33
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
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
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Douglas, Nataki C; Papaioannou, Virginia E (2013) The T-box transcription factors TBX2 and TBX3 in mammary gland development and breast cancer. J Mammary Gland Biol Neoplasia 18:143-7
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Saadi, Irfan; Das, Pragnya; Zhao, Minglian et al. (2013) Msx1 and Tbx2 antagonistically regulate Bmp4 expression during the bud-to-cap stage transition in tooth development. Development 140:2697-702
Lugani, Francesca; Arora, Ripla; Papeta, Natalia et al. (2013) A retrotransposon insertion in the 5' regulatory domain of Ptf1a results in ectopic gene expression and multiple congenital defects in Danforth's short tail mouse. PLoS Genet 9:e1003206
Ballim, Reyna Deeya; Mendelsohn, Cathy; Papaioannou, Virginia E et al. (2012) The ulnar-mammary syndrome gene, Tbx3, is a direct target of the retinoic acid signaling pathway, which regulates its expression during mouse limb development. Mol Biol Cell 23:2362-72

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