Tbx1 functions in pharyngeal arch and cardiovascular development

Caprio, Cinzia (2014). Tbx1 functions in pharyngeal arch and cardiovascular development. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0000ef0b


Tbx1, a gene encoding a T-box transcription factor, is required for embryonic development in humans and mice. Half dosage of this gene causes most of the features of the DiGeorge or Velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities. Here we show that genetic ablation of Trp53 or pharmacological inhibition of its protein product p53 rescues almost completely aortic arch defects and significantly ameliorates outflow tract defects of Tbx1 mouse mutants. Trp53 deletion rescues the cell proliferation deficit in the second heart field of Tbx1 mutants. In addition, and surprisingly, Tbx1 and p53 proteins can be found on neighboring sites on chromatin, suggesting that they share a set of target genes. In a search for shared targets, we found that the expression of Gbx2, a gene that interacts with Tbx1 during development of the aortic arch arteries, is down regulated by Tbx1 heterozygosity and rescued by Trp53 heterozygosity. In addition, Tbx1 and p53 occupy the Gbx2 gene, indicating that both contribute to its regulation.

Overall our data identify unexpected interactions between Tbx1 and Trp53 and provide a proof of principle that developmental defects associated with reduced dosage of Tbx1 can be rescued pharmacologically.

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