Letter | Published:

Dystrophin–glycoprotein complex sequesters Yap to inhibit cardiomyocyte proliferation

Nature volume 547, pages 227231 (13 July 2017) | Download Citation

Abstract

The regenerative capacity of the adult mammalian heart is limited, because of the reduced ability of cardiomyocytes to progress through mitosis1. Endogenous cardiomyocytes have regenerative capacity at birth but this capacity is lost postnatally, with subsequent organ growth occurring through cardiomyocyte hypertrophy2,3. The Hippo pathway, a conserved kinase cascade, inhibits cardiomyocyte proliferation in the developing heart to control heart size and prevents regeneration in the adult heart4,5. The dystrophin–glycoprotein complex (DGC), a multicomponent transmembrane complex linking the actin cytoskeleton to extracellular matrix, is essential for cardiomyocyte homeostasis. DGC deficiency in humans results in muscular dystrophy, including the lethal Duchenne muscular dystrophy. Here we show that the DGC component dystroglycan 1 (Dag1) directly binds to the Hippo pathway effector Yap to inhibit cardiomyocyte proliferation in mice. The Yap–Dag1 interaction was enhanced by Hippo-induced Yap phosphorylation, revealing a connection between Hippo pathway function and the DGC. After injury, Hippo-deficient postnatal mouse hearts maintained organ size control by repairing the defect with correct dimensions, whereas postnatal hearts deficient in both Hippo and the DGC showed cardiomyocyte overproliferation at the injury site. In the hearts of mature Mdx mice (which have a point mutation in Dmd)—a model of Duchenne muscular dystrophy—Hippo deficiency protected against overload-induced heart failure.

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References

  1. 1.

    , & Mending broken hearts: cardiac development as a basis for adult heart regeneration and repair. Nat. Rev. Mol. Cell Biol. 14, 529–541 (2013)

  2. 2.

    et al. Transient regenerative potential of the neonatal mouse heart. Science 331, 1078–1080 (2011)

  3. 3.

    et al. Dynamics of cell generation and turnover in the human heart. Cell 161, 1566–1575 (2015)

  4. 4.

    et al. Hippo signaling impedes adult heart regeneration. Development 140, 4683–4690 (2013)

  5. 5.

    et al. Hippo pathway inhibits Wnt signaling to restrain cardiomyocyte proliferation and heart size. Science 332, 458–461 (2011)

  6. 6.

    . et al. Actin cytoskeletal remodeling with protrusion formation is essential for heart regeneration in Hippo-deficient mice. Sci. Signal. 8, ra41 (2015)

  7. 7.

    et al. Localization of the mdx mutation within the mouse dystrophin gene. EMBO J. 7, 3017–3021 (1988)

  8. 8.

    , , , & Combined effects of microtopography and cyclic strain on vascular smooth muscle cell orientation. J. Biomech. 41, 762–769 (2008)

  9. 9.

    , & Current understanding of molecular pathology and treatment of cardiomyopathy in Duchenne muscular dystrophy. Molecules 20, 8823–8855 (2015)

  10. 10.

    et al. Combination of tumor necrosis factor-α ablation and matrix metalloproteinase inhibition prevents heart failure after pressure overload in tissue inhibitor of metalloproteinase-3 knock-out mice. Circ. Res. 97, 380–390 (2005)

  11. 11.

    et al. Dystrophin-deficient myocardium is vulnerable to pressure overload in vivo. Cardiovasc. Res. 50, 509–515 (2001)

  12. 12.

    , , , & Contribution of the different modules in the utrophin carboxy-terminal region to the formation and regulation of the DAP complex. FEBS Lett. 471, 229–234 (2000)

  13. 13.

    , , , & A coordinated phosphorylation by Lats and CK1 regulates YAP stability through SCFβ-TRCP. Genes Dev. 24, 72–85 (2010)

  14. 14.

    et al. Alpha-catenins control cardiomyocyte proliferation by regulating Yap activity. Circ. Res. 116, 70–79 (2015)

  15. 15.

    , & Transduction of mechanical and cytoskeletal cues by YAP and TAZ. Nat. Rev. Mol. Cell Biol. 13, 591–600 (2012)

  16. 16.

    et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science 351, 400–403 (2016)

  17. 17.

    et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science 351, 403–407 (2016)

  18. 18.

    et al. In vivo gene editing in dystrophic mouse muscle and muscle stem cells. Science 351, 407–411 (2016)

  19. 19.

    , , & Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis. Model. Mech. 8, 195–213 (2015)

  20. 20.

    et al. No evidence for cardiomyocyte number expansion in preadolescent mice. Cell 163, 1026–1036 (2015)

  21. 21.

    Simultaneous assessment of cardiomyocyte DNA synthesis and ploidy: a method to assist quantification of cardiomyocyte regeneration and turnover. J. Vis. Exp. (111) e53979 ( 2016)

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Acknowledgements

This project was supported in part by an Intellectual and Developmental Disability Research Center grant (1U54 HD083092) from the Eunice Kennedy Shriver National Institute of Child Health & Human Development; the Mouse Phenotyping Core at Baylor College of Medicine with funding from the National Institutes of Health (U54 HG006348); and grants from the National Institutes of Health (DE 023177, HL 127717, HL 130804, and HL 118761 to J.F.M.) and the Vivian L. Smith Foundation (to J.F.M.). J.F.M. was supported by the Transatlantic Network of Excellence Award LeDucq Foundation Transatlantic Networks of Excellence in Cardiovascular Research 14CVD01. T.H. was supported by the American Heart Association Scientist Development Grant (16SDG26460001). We thank N. Stancel of the Texas Heart Institute for editorial assistance.

Author information

Affiliations

  1. Cardiomyocyte Renewal Laboratory, Texas Heart Institute, Houston, Texas 77030, USA

    • Yuka Morikawa
    • , Todd Heallen
    • , Yang Xiao
    •  & James F. Martin
  2. Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, Texas 77030, USA

    • John Leach
    •  & James F. Martin
  3. Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA

    • James F. Martin
  4. Cardiovascular Research Institute, Baylor College of Medicine, Houston, Texas 77030, USA

    • James F. Martin

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Contributions

J.F.M. and Y.M. conceived the project and designed the experiments. Y.M. performed experiments and analysed data. T.H. performed immunoprecipitation experiments, protein-binding assay and western blotting. J.L. performed cardiac function analysis and AAV9 viral studies. Y.X. performed several immunohistochemical studies. J.F.M., Y.M. and J.L. performed statistical analyses. J.F.M. supervised the project and analysed data. Y.M. and J.F.M. wrote the manuscript. All authors edited and approved the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to James F. Martin.

Reviewer Information Nature thanks K. Yutzey and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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    Supplementary Figure

    This file contains the uncropped scans with size marker indications.

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https://doi.org/10.1038/nature22979

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