TY - JOUR
T1 - Transcription factor TEAD1 is essential for vascular development by promoting vascular smooth muscle differentiation
AU - Wen, Tong
AU - Liu, Jinhua
AU - He, Xiangqin
AU - Dong, Kunzhe
AU - Hu, Guoqing
AU - Yu, Luyi
AU - Yin, Qin
AU - Osman, Islam
AU - Peng, Jingtian
AU - Zheng, Zeqi
AU - Xin, Hongbo
AU - Fulton, David J
AU - Du, Quansheng
AU - Zhang, Wei
AU - Zhou, Jiliang
N1 - Publisher Copyright:
© 2019, ADMC Associazione Differenziamento e Morte Cellulare.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - TEAD1 (TEA domain transcription factor 1), a transcription factor known for the functional output of Hippo signaling, is important for tumorigenesis. However, the role of TEAD1 in the development of vascular smooth muscle cell (VSMC) is unknown. To investigate cell-specific role of Tead1, we generated cardiomyocyte (CMC) and VSMC-specific Tead1 knockout mice. We found CMC/VSMC-specific deletion of Tead1 led to embryonic lethality by E14.5 in mice due to hypoplastic cardiac and vascular walls, as a result of impaired CMC and VSMC proliferation. Whole transcriptome analysis revealed that deletion of Tead1 in CMCs/VSMCs downregulated expression of muscle contractile genes and key transcription factors including Pitx2c and myocardin. In vitro studies demonstrated that PITX2c and myocardin rescued TEAD1-dependent defects in VSMC differentiation. We further identified Pitx2c as a novel transcriptional target of TEAD1, and PITX2c exhibited functional synergy with myocardin by directly interacting with myocardin, leading to augment the differentiation of VSMC. In summary, our study reveals a critical role of Tead1 in cardiovascular development in mice, but also identifies a novel regulatory mechanism, whereby Tead1 functions upstream of the genetic regulatory hierarchy for establishing smooth muscle contractile phenotype.
AB - TEAD1 (TEA domain transcription factor 1), a transcription factor known for the functional output of Hippo signaling, is important for tumorigenesis. However, the role of TEAD1 in the development of vascular smooth muscle cell (VSMC) is unknown. To investigate cell-specific role of Tead1, we generated cardiomyocyte (CMC) and VSMC-specific Tead1 knockout mice. We found CMC/VSMC-specific deletion of Tead1 led to embryonic lethality by E14.5 in mice due to hypoplastic cardiac and vascular walls, as a result of impaired CMC and VSMC proliferation. Whole transcriptome analysis revealed that deletion of Tead1 in CMCs/VSMCs downregulated expression of muscle contractile genes and key transcription factors including Pitx2c and myocardin. In vitro studies demonstrated that PITX2c and myocardin rescued TEAD1-dependent defects in VSMC differentiation. We further identified Pitx2c as a novel transcriptional target of TEAD1, and PITX2c exhibited functional synergy with myocardin by directly interacting with myocardin, leading to augment the differentiation of VSMC. In summary, our study reveals a critical role of Tead1 in cardiovascular development in mice, but also identifies a novel regulatory mechanism, whereby Tead1 functions upstream of the genetic regulatory hierarchy for establishing smooth muscle contractile phenotype.
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U2 - 10.1038/s41418-019-0335-4
DO - 10.1038/s41418-019-0335-4
M3 - Article
C2 - 31024075
AN - SCOPUS:85064932597
SN - 1350-9047
VL - 26
SP - 2790
EP - 2806
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 12
ER -