Barx2 and Pax7 Have Antagonistic Functions in Regulation of Wnt Signaling and Satellite Cell Differentiation

Authors

  • Lizhe Zhuang,

    1. Department of Clinical Pharmacology, Flinders University, Adelaide, South Australia, Australia
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  • Julie-Ann Hulin,

    1. Department of Clinical Pharmacology, Flinders University, Adelaide, South Australia, Australia
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  • Anastasia Gromova,

    1. Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA
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  • Thi Diem Tran Nguyen,

    1. Department of Clinical Pharmacology, Flinders University, Adelaide, South Australia, Australia
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  • Ruth T. Yu,

    1. Gene Expression Laboratory and Salk Institute, La Jolla, California, USA
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  • Christopher Liddle,

    1. The Storr Liver Unit, Westmead Millennium Institute and University of Sydney, Westmead Hospital, Westmead, New South Wales, Australia
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  • Michael Downes,

    1. Gene Expression Laboratory and Salk Institute, La Jolla, California, USA
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  • Ronald M. Evans,

    1. Gene Expression Laboratory and Salk Institute, La Jolla, California, USA
    2. Howard Hughes Medical Institute, Salk Institute, La Jolla, California, USA
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  • Helen P. Makarenkova,

    Corresponding author
    1. Department of Cell and Molecular Biology, The Scripps Research Institute, La Jolla, California, USA
    2. The Neurosciences Institute, San Diego, California, USA
    • Correspondence: Robyn Meech, Ph.D., Department of Clinical Pharmacology, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia. Fax: 61-8-8204-5114; e-mail: robyn.meech@flinders.edu.au; or Helen P. Makarenkova, Ph.D., Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Fax: 858-784-2646; e-mail: hmakarenk@scripps.edu

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  • Robyn Meech

    Corresponding author
    1. Department of Clinical Pharmacology, Flinders University, Adelaide, South Australia, Australia
    • Correspondence: Robyn Meech, Ph.D., Department of Clinical Pharmacology, Flinders University, Bedford Park, Adelaide, South Australia 5042, Australia. Fax: 61-8-8204-5114; e-mail: robyn.meech@flinders.edu.au; or Helen P. Makarenkova, Ph.D., Department of Cell and Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA. Fax: 858-784-2646; e-mail: hmakarenk@scripps.edu

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Abstract

The canonical Wnt signaling pathway is critical for myogenesis and can induce muscle progenitors to switch from proliferation to differentiation; how Wnt signals integrate with muscle-specific regulatory factors in this process is poorly understood. We previously demonstrated that the Barx2 homeobox protein promotes differentiation in cooperation with the muscle regulatory factor (MRF) MyoD. Pax7, another important muscle homeobox factor, represses differentiation. We now identify Barx2, MyoD, and Pax7 as novel components of the Wnt effector complex, providing a new molecular pathway for regulation of muscle progenitor differentiation. Canonical Wnt signaling induces Barx2 expression in muscle progenitors and perturbation of Barx2 leads to misregulation of Wnt target genes. Barx2 activates two endogenous Wnt target promoters as well as the Wnt reporter gene TOPflash, the latter synergistically with MyoD. Moreover, Barx2 interacts with the core Wnt effectors β-catenin and T cell-factor 4 (TCF4), is recruited to TCF/lymphoid enhancer factor sites, and promotes recruitment of β-catenin. In contrast, Pax7 represses the Wnt reporter gene and antagonizes the activating effect of Barx2. Pax7 also binds β-catenin suggesting that Barx2 and Pax7 may compete for interaction with the core Wnt effector complex. Overall, the data show for the first time that Barx2, Pax7, and MRFs can act as direct transcriptional effectors of Wnt signals in myoblasts and that Barx2 and Wnt signaling participate in a regulatory loop. We propose that antagonism between Barx2 and Pax7 in regulation of Wnt signaling may help mediate the switch from myoblast proliferation to differentiation. Stem Cells 2014;32:1661–1673

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