Tbx20 Transcription Factor Is a Downstream Mediator for Bone Morphogenetic Protein-10 in Regulating Cardiac Ventricular Wall Development and Function

R Mark Payne,Weidong Yong,Wuqiang Zhu,Hanying Chen,Chen-Leng Cai,Wenjun Zhang,Hongbo Xin,Gregory R Wagner,Yunlong Liu,Weinian Shou,Loren J Field,Yong Wang

doi:10.1074/jbc.m111.279679

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.

Highlights

Bone morphogenetic protein 10 (BMP10) is an important cardiac cytokine and has a critical role in ventricular development
Our findings suggest that T-box 20 (Tbx20) is one of the direct downstream transcription factors regulated by BMP10, and this BMP10-Tbx20 signaling cascade is important for cardiac ventricular wall formation and maturation
The majority of the cardiogenic transcription factors in the BMP10 transgenic hearts were expressed at similar levels compared with nontransgenic control hearts with a few exceptions such as Tbx20, activating transcription factor 3 (Atf3), Smad6, Smad7, and Smad8

Summary

Introduction

BMP10 is an important cardiac cytokine and has a critical role in ventricular development. Significance: BMP10-Tbx signaling cascade is important for ventricular wall development and maturation. We had demonstrated that BMP10 is a key regulator for ventricular chamber formation, growth, and maturation. The molecular mechanism(s) by which BMP10 regulates ventricle wall growth and maturation is still largely unknown. T-box 20 (Tbx20), a cardiac transcription factor, was significantly up-regulated in ␣MHC-BMP10 transgenic hearts, which was validated by quantitative RT-PCR and in situ hybridization. Overexpression of Tbx in myocardium led to dilated cardiomyopathy that exhibited ventricular hypertrabeculation and an abnormal muscular septum, which phenocopied genetically modified mice with elevated BMP10 levels. Our findings demonstrate that the BMP10-Tbx signaling cascade is important for ventricular wall development and maturation

Methods

Results

Conclusion