Genetic Analysis of Tbx1 in Ear Disorders

Project: Research project

Project Details


[unreadable] DESCRIPTION (provided by applicant): Velo-cardio-facial syndrome/DiGeorge syndrome (VCFS/DGS) is a congenital anomaly disorder associated with hemizygous 1.5-3 Mb 22ql 1 deletions. Most patients have learning disabilities, craniofacial anomalies, outflow tract heart defects and ear disorders. Over 24 genes lie in the 1.5 Mb interval that is deleted. The 1.5 Mb region is conserved on mouse chromosome 16. By taking genetics approaches, we recently found that one of the genes, termed Tbxl, a member of the T-box family of transcription factor genes, is a strong candidate for the syndrome in mouse models. We targeted the Tbxl gene for inactivation and found that while hemizygous mice were mildly affected, homozygous mice died in the perinatal period with malformations that were particularly striking in their magnitude. They had cleft palate, major cardiovascular defects, no thymus or parathyroid glands and no outer, middle or inner ear. We are interested in determining the role of Tbxl in ear development and disease. Both the otic vesicle epithelium and surrounding periotic mesenchyme interact to form the inner ear. The fact that Tbxl is highly expressed in both tissues, suggests that it might play dual roles in patterning the inner ear. We hypothesize that Tbxl encodes a transcription factor whose dual expression is required for ear development. For Specific Aim 1, we will determine the role of Tbxl in the otic vesicle epithelium and separately in the periotic mesenchyme by generating conditional alleles in the mouse. For Specific Aim 2, we will determine whether Tbxl is a transcriptional activator or repressor and define the Tbxl domains required for transcription factor activity. Two other T-box genes, Tbx2 and Tbx3, are co-expressed in the otic vesicle during development. The basis for Tbxl function may lie in its requirement to form functional homodimers or heterodimers. We will determine whether Tbxl protein can functionally interact with Tbx2 or Tbx3. Many genes required to form the ear have been identified. We will take a candidate gene approach to determine the role of Tbxl in altering the expression of downstream target genes in the ears of mutant mice as Specific Aim 3. By achieving the goals of these specific aims, we will understand the role of Tbxl in normal ear development and disease. [unreadable] [unreadable]
Effective start/end date12/1/0211/30/14


  • Genetics
  • Speech and Hearing
  • Molecular Biology
  • Medicine(all)
  • Neuroscience(all)


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