title: p53 Suppression partially rescues the mutant phenotype in mouse models of DiGeorge syndrome.
abstract: T-box 1 (Tbx1), a gene encoding a T-box transcription factor, is required for embryonic development in humans and mice. Half dosage of this gene in humans causes most of the features of the DiGeorge or Velocardiofacial syndrome phenotypes, including aortic arch and cardiac outflow tract abnormalities. Here we found a strong genetic interaction between Tbx1 and transformation related protein 53 (Trp53). Indeed, genetic ablation of Trp53, or pharmacological inhibition of its protein product p53, rescues significantly the cardiovascular defects of Tbx1 heterozygous and hypomorphic mutants. We found that the Tbx1 and p53 proteins do not interact directly but both occupy a genetic element of Gbx2, which is required for aortic arch and cardiac outflow tract development, and is a known genetic interactor of Tbx1. We found that Gbx2 expression is down-regulated in Tbx1(+/-) embryos and is restored to normal levels in Tbx1(+/-);Trp53(+/-) embryos. In addition, we found that the genetic element that binds both Tbx1 and p53 is highly enriched in H3K27 trimethylation, and upon p53 suppression H3K27me3 levels are reduced, along with Ezh2 enrichment. This finding suggests that the rescue of Gbx2 expression in Tbx1(+/-);Trp53(+/-) embryos is due to reduction of repressive chromatin marks. Overall our data identify unexpected genetic interactions between Tbx1 and Trp53 and provide a proof of principle that developmental defects associated with reduced dosage of Tbx1 can be rescued pharmacologically.
authors.affiliation: Open University PhD Program, Consiglio Nazionale delle Ricerche Institute of Genetics and Biophysics Adriano Buzzati Traverso, 80131 Naples, Italy; and.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Caprio
authors.affiliation: Consiglio Nazionale delle Ricerche Institute of Genetics and Biophysics Adriano Buzzati Traverso, 80131 Naples, Italy; and Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy antonio.baldini@igb.cnr.it.
authors.forename: Antonio
authors.initials: A
authors.lastname: Baldini
mesh_terms: D000818:Animals; D001158:Arteries / Q000002:abnormalities / Q000196:embryology; D052160:Benzothiazoles / Q000494:pharmacology; D001934:Branchial Region / Q000002:abnormalities; D002843:Chromatin / Q000378:metabolism; D003433:Crosses, Genetic; D004062:DiGeorge Syndrome / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D004622:Embryo, Mammalian / Q000002:abnormalities / Q000473:pathology; D004843:Epistasis, Genetic / Q000187:drug effects; D005260:Female; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011485:Protein Binding / Q000187:drug effects; D020825:T-Box Domain Proteins / Q000235:genetics; D014050:Toluene / Q000031:analogs & derivatives / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D052160:Benzothiazoles; D002843:Chromatin; C513182:Gbx2 protein, mouse; D018398:Homeodomain Proteins; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse; D016159:Tumor Suppressor Protein p53; D014050:Toluene; C121565:pifithrin
keywords: Tbx1 and second heart field; pharyngeal arch artery development