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Transcription factor TEAD1 is essential for vascular development by promoting vascular smooth muscle differentiation

Abstract

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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Acknowledgements

We thank Dr. Nicole Winston for a critical reading of the paper. We also thank Dr. Guangyu Wu’s laboratory for their help to generate Pitx2c-pET28 plasmid. The work at the J.Z. laboratory is supported by a grant from the National Heart, Lung, and Blood Institute, NIH (HL132164). J.Z. is a recipient of Established Investigator Award (17EIA33460468) from the American Heart Association. K.D. and I.O. are supported by postdoctoral fellowships (19POST34450071 and 18POST34030400, respectively) from the American Heart Association.

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Correspondence to Wei Zhang or Jiliang Zhou.

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