Role and Interactions of TBX1 During Development

Recent Research - Basic Science

Unless you've been asleep at our 22q11.2DS Society meetings for the past few years you can't have failed to pick up that TBX1 haploinsufficiency recapitulates many of the structural defects seen in the syndrome. Recent studies significantly extend our understanding of the role and interactions of TBX1 during development.

In one, Antonio Baldini and colleagues followed up some of their previous work demonstrating how TBX1 regulated the balance between proliferation and differentiation in stem/progenitor cell lines. Noting how the erstwhile 'molecule of the year' TRP53 had similar effects they asked whether Tbx1 and Trp53 operated in the same genetic pathway. The results were startling: loss of one copy of Trp53 significantly ameliorated many of the heart and vascular defects seen with Tbx1 haploinsufficiency. They went on to demonstrate that, rather than interacting directly as a protein complex, both factors regulated the expression of Gbx2, itself known to be vital for heart development. Furthermore, pharmacological inhibition of the TRP53 pathway in the context of Tbx1 haploinsufficiency had much the same effect, essentially demonstrating a form of drug intervention, at least in a mouse model.

Caprio C, Baldini A. p53 suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome. Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):13385-90. Pubmed Link

A second study, a long standing notion concerning TBX1 is challenged. Hiromi Yanagisawa's team undertook an analysis of skeletal defects in Tbx1 (fully null) mutants. They found a range of defects similar to a disorder caused by loss of the transcription factor RUNX2, called cleidocranial dysplasia (CCD). The main abnormalities were short stature, absence of hyoid bone, failed closure of fontanelle, bifid xiphoid process and hypoplasia of clavicle and zygomatic arch. When they examined tissue specific mutants they found that knockout of Tbx1 in the neural crest lineage partially recapitulated these effects, despite previous claims that Tbx1 is never expressed in these cells. There was an additional role for Tbx1 in the mesoderm. While Tbx1 heterozygotes were not reported to have these defects, it is quite possible that TBX1 haploinsufficiency in humans predisposes to a CCD-like series of malformations.

Loss of Tbx1 induces bone phenotypes similar to cleidocranial dysplasia. Funato N, Nakamura M, Richardson JA, Srivastava D, Yanagisawa H. Hum Mol Genet. 2014 Sep 10. Pubmed Link