title: Tbx20 transcription factor is a downstream mediator for bone morphogenetic protein-10 in regulating cardiac ventricular wall development and function.
abstract: Bone morphogenetic protein 10 (BMP10) belongs to the TGFβ-superfamily. Previously, we had demonstrated that BMP10 is a key regulator for ventricular chamber formation, growth, and maturation. Ablation of BMP10 leads to hypoplastic ventricular wall formation, and elevated levels of BMP10 are associated with abnormal ventricular trabeculation/compaction and wall maturation. However, the molecular mechanism(s) by which BMP10 regulates ventricle wall growth and maturation is still largely unknown. In this study, we sought to identify the specific transcriptional network that is potentially mediated by BMP10. We analyzed and compared the gene expression profiles between α-myosin heavy chain (αMHC)-BMP10 transgenic hearts and nontransgenic littermate controls using Affymetrix mouse exon arrays. T-box 20 (Tbx20), a cardiac transcription factor, was significantly up-regulated in αMHC-BMP10 transgenic hearts, which was validated by quantitative RT-PCR and in situ hybridization. Ablation of BMP10 reduced Tbx20 expression specifically in the BMP10-expressing region of the developing ventricle. In vitro promoter analysis demonstrated that BMP10 was able to induce Tbx20 promoter activity through a conserved Smad binding site in the Tbx20 promoter proximal region. Furthermore, overexpression of Tbx20 in myocardium led to dilated cardiomyopathy that exhibited ventricular hypertrabeculation and an abnormal muscular septum, which phenocopied genetically modified mice with elevated BMP10 levels. Taken together, our findings demonstrate that the BMP10-Tbx20 signaling cascade is important for ventricular wall development and maturation.
authors: Riley Heart Research Center, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA.
authors: Wenjun
authors: W
authors: Zhang
authors: Hanying
authors: H
authors: Chen
authors: Yong
authors: Y
authors: Wang
authors: Weidong
authors: W
authors: Yong
authors: Wuqiang
authors: W
authors: Zhu
authors: Yunlong
authors: Y
authors: Liu
authors: Gregory R
authors: GR
authors: Wagner
authors: R Mark
authors: RM
authors: Payne
authors: Loren J
authors: LJ
authors: Field
authors: Hongbo
authors: H
authors: Xin
authors: Chen-Leng
authors: CL
authors: Cai
authors: Weinian
authors: W
authors: Shou
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis* / Q000235:genetics; D002311:Cardiomyopathy, Dilated / Q000196:embryology / Q000235:genetics / Q000473:pathology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology*; D006345:Heart Septal Defects, Ventricular / Q000196:embryology / Q000235:genetics / Q000473:pathology; D006352:Heart Ventricles / Q000196:embryology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D020218:Response Elements / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D024723:Ventricular Myosins / Q000235:genetics / Q000378:metabolism; D054088:Ventricular Septum / Q000196:embryology / Q000473:pathology
chemical_list: C119152:Bmp10 protein, mouse; D019485:Bone Morphogenetic Proteins; D020825:T-Box Domain Proteins; C486013:Tbx20 protein, mouse; D024723:Ventricular Myosins; D018995:Myosin Heavy Chains