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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD046767-02
Application #
6989787
Study Section
Development - 1 Study Section (DEV)
Program Officer
Javois, Lorette Claire
Project Start
2004-12-15
Project End
2009-11-30
Budget Start
2005-12-01
Budget End
2006-11-30
Support Year
2
Fiscal Year
2006
Total Cost
$328,471
Indirect Cost
Name
University of Utah
Department
Type
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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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:
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