title: Tbx1 is regulated by tissue-specific forkhead proteins through a common Sonic hedgehog-responsive enhancer.
abstract: Haploinsufficiency of Tbx1 is likely a major determinant of cardiac and craniofacial birth defects associated with DiGeorge syndrome. Although mice deficient in Tbx1 exhibit pharyngeal and aortic arch defects, the developmental program and mechanisms through which Tbx1 functions are relatively unknown. We identified a single cis-element upstream of Tbx1 that recognized winged helix/forkhead box (Fox)-containing transcription factors and was essential for regulation of Tbx1 transcription in the pharyngeal endoderm and head mesenchyme. The Tbx1 regulatory region was responsive to signaling by Sonic hedgehog (Shh) in vivo. We show that Shh is necessary for aortic arch development, similar to Tbx1, and is also required for expression of Foxa2 and Foxc2 in the pharyngeal endoderm and head mesenchyme, respectively. Foxa2, Foxc1, or Foxc2 could bind and activate transcription through the critical cis-element upstream of Tbx1, and Foxc proteins were required, within their expression domains, for Tbx1 transcription in vivo. We propose that Tbx1 is a direct transcriptional target of Fox proteins and that Fox proteins may serve an intermediary role in Shh regulation of Tbx1.
authors.affiliation: Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390-9148, USA. Hiroyuki.Yamagishi@UTSouthwestern.edu
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamagishi
authors.forename: Jun
authors.initials: J
authors.lastname: Maeda
authors.forename: Tonghuan
authors.initials: T
authors.lastname: Hu
authors.forename: John
authors.initials: J
authors.lastname: McAnally
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Conway
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kume
authors.forename: Erik N
authors.initials: EN
authors.lastname: Meyers
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamagishi
authors.forename: Deepak
authors.initials: D
authors.lastname: Srivastava
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D004062:DiGeorge Syndrome / Q000196:embryology / Q000235:genetics; D004195:Disease Models, Animal; D004742:Enhancer Elements, Genetic; D051858:Forkhead Transcription Factors; D018507:Gene Expression Regulation, Developmental; D053823:Hedgehog Proteins; D051542:Hepatocyte Nuclear Factor 3-beta; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008954:Models, Biological; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology*; D009928:Organ Specificity; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics* / Q000502:physiology*; D015534:Trans-Activators / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; C496502:FOXA2 protein, human; C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; C496503:Foxa2 protein, mouse; C112890:Foxc1 protein, mouse; D053823:Hedgehog Proteins; D009687:Nuclear Proteins; C509239:SHH protein, human; C465570:Shh protein, mouse; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; C491573:Tbx1 protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C082078:mesenchyme fork head 1 protein; D051542:Hepatocyte Nuclear Factor 3-beta