T-box genes encode a family of transcription factors that are expressed in multiple tissues and function in diverse genetic pathways during development. Mutations in humanTBX3 and TBX5 result in autosomal dominant, ulnar-mammary (UMS) and Holt-Oram syndromes, respectively, and TBX1 deficiency contributes to human deletion 22q11 syndromes. Patients with UMS have congenital limb, apocrine gland, tooth, and genital abnormalities. TBX3 loss-of-function mutations that disrupt DNA binding may cause some cases of UMS. Other mutations occur in regions required for protein-protein interactions or disrupt regulatory (activator or repressor) function. No genotype-phenotype correlations have been detected in affected humans. Murine Tbx3 null heterozygotes do not manifest the UMS phenotype and most homozygous null mutants die in midgestation. Thus, determining the specific effects of Tbx3 deficiency in different regions of the developing limb, or in other organs, requires conditional mutation of murine Tbx3. The goal of this project is to generate conditional mouse models of Tbx3 disruption and dysfunction and examine the molecular and cellular mechanisms by which mutations of Tbx3 cause birth defects, with an emphasis on the limb. We will disrupt Tbx3 function conditionally and use recombinase -mediated cassette exchange to mutate distinct Tbx3 protein functional domains. Alterations in gene expression, cellular differentiation, migration, proliferation and survival will be examined. We have already discovered a novel phenotype due to dominant negative effects of an Exon 7 mutation and propose to analyze its transcriptional function. Genotype -phenotype correlations may also be defined to direct new investigations in humans with UMS. The flexible model system we propose will be a valuable tool for developmental studies of many organs and lead to a deeper understanding of the genetic and molecular bases of congenital anomalies in humans.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Research Project (R01)
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Development - 1 Study Section (DEV)
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Javois, Lorette Claire
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University of Utah
Salt Lake City
United States
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Russell, Ronan; Ilg, Marcus; Lin, Qiong et al. (2015) A Dynamic Role of TBX3 in the Pluripotency Circuitry. Stem Cell Reports 5:1155-1170
Cioffi, Michele; Vallespinos-Serrano, Mireia; Trabulo, Sara M et al. (2015) MiR-93 Controls Adiposity via Inhibition of Sirt7 and Tbx3. Cell Rep 12:1594-605
Kumar P, Pavan; Franklin, Sarah; Emechebe, Uchenna et al. (2014) TBX3 regulates splicing in vivo: a novel molecular mechanism for Ulnar-mammary syndrome. PLoS Genet 10:e1004247
Kumar P, Pavan; Emechebe, Uchenna; Smith, Richard et al. (2014) Coordinated control of senescence by lncRNA and a novel T-box3 co-repressor complex. Elife 3:
Frank, Deborah U; Emechebe, Uchenna; Thomas, Kirk R et al. (2013) Mouse TBX3 mutants suggest novel molecular mechanisms for Ulnar-mammary syndrome. PLoS One 8:e67841
Frank, Deborah U; Carter, Kandis L; Thomas, Kirk R et al. (2012) Lethal arrhythmias in Tbx3-deficient mice reveal extreme dosage sensitivity of cardiac conduction system function and homeostasis. Proc Natl Acad Sci U S A 109:E154-63
Murashima, Aki; Miyagawa, Shinichi; Ogino, Yukiko et al. (2011) Essential roles of androgen signaling in Wolffian duct stabilization and epididymal cell differentiation. Endocrinology 152:1640-51