title: Tbx1 is regulated by forkhead proteins in the secondary heart field.
abstract: Transcriptional regulation in a tissue-specific and quantitative manner is essential for developmental events, including those involved in cardiovascular morphogenesis. Tbx1 is a T-box-containing transcription factor that is responsible for many of the defects observed in 22q11 deletion syndrome in humans. Tbx1 is expressed in the secondary heart field (SHF) and is essential for cardiac outflow tract (OFT) development. We previously reported that Tbx1 is regulated by sonic hedgehog by means of forkhead (Fox) transcription factors in the head mesenchyme and pharyngeal endoderm, but how it is regulated in the SHF is unknown. Here, we show that Tbx1 expression in the SHF is regulated by Fox proteins through a combination of two evolutionarily conserved Fox binding sites in a dose-dependent manner. Cell fate analysis using the Tbx1 enhancer suggests that SHF-derived Tbx1-expressing cells contribute extensively to the right ventricular myocardium as well as the OFT during early development and ultimately give rise to the right ventricular infundibulum, pulmonary trunk, and pulmonary valves. These results suggest that Fox proteins are involved in most, if not all, Tbx1 expression domains and that Tbx1 marks a subset of SHF-derived cells, particularly those that uniquely contribute to the right-sided outflow tract and proximal pulmonary artery.
authors.affiliation: Department of Pediatrics, Division of Pediatric Cardiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamagishi
authors.forename: John
authors.initials: J
authors.lastname: McAnally
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamagishi
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D001665:Binding Sites; D004742:Enhancer Elements, Genetic; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000254:growth & development*; D006352:Heart Ventricles / Q000737:chemistry / Q000166:cytology / Q000254:growth & development; D051379:Mice; D008822:Mice, Transgenic; D032383:Myocytes, Cardiac / Q000737:chemistry / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: D051858:Forkhead Transcription Factors; D020825:T-Box Domain Proteins; C491573:Tbx1 protein, mouse