The Hippo pathway controls myofibril assembly and muscle fiber growth by regulating sarcomeric gene expression

  1. Aynur Kaya-Çopur  Is a corresponding author
  2. Fabio Marchiano
  3. Marco Y Hein
  4. Daniel Alpern
  5. Julie Russeil
  6. Nuno Miguel Luis
  7. Matthias Mann
  8. Bart Deplancke
  9. Bianca H Habermann
  10. Frank Schnorrer  Is a corresponding author
  1. Aix Marseille University, CNRS, IDBM, France
  2. Max Planck Institute of Biochemistry, Germany
  3. École Polytechnique Fédérale de Lausanne (EPFL), Switzerland
  4. Aix Marseille University, CNRS, France

Abstract

Skeletal muscles are composed of gigantic cells called muscle fibers, packed with force-producing myofibrils. During development the size of individual muscle fibers must dramatically enlarge to match with skeletal growth. How muscle growth is coordinated with growth of the contractile apparatus is not understood. Here, we use the large Drosophila flight muscles to mechanistically decipher how muscle fiber growth is controlled. We find that regulated activity of core members of the Hippo pathway is required to support flight muscle growth. Interestingly, we identify Dlg5 and Slmap as regulators of the STRIPAK phosphatase, which negatively regulates Hippo to enable post-mitotic muscle growth. Mechanistically, we show that the Hippo pathway controls timing and levels of sarcomeric gene expression during development and thus regulates the key components that physically mediate muscle growth. Since Dlg5, STRIPAK and the Hippo pathway are conserved a similar mechanism may contribute to muscle or cardiomyocyte growth in humans.

Data availability

Sequencing data have been deposited in GEO under accession code GSE158957

The following data sets were generated

Article and author information

Author details

  1. Aynur Kaya-Çopur

    Muscle Dynamics, Aix Marseille University, CNRS, IDBM, Marseille, France
    For correspondence
    aynur.KAYA-COPUR@univ-amu.fr
    Competing interests
    The authors declare that no competing interests exist.
  2. Fabio Marchiano

    Computational Biology, Aix Marseille University, CNRS, IDBM, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Marco Y Hein

    Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9490-2261
  4. Daniel Alpern

    Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  5. Julie Russeil

    Institute of Bioengineering, School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
  6. Nuno Miguel Luis

    Institut de Biologie du Développement de Marseille, Aix Marseille University, CNRS, Marseille, France
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5438-9638
  7. Matthias Mann

    Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-1292-4799
  8. Bart Deplancke

    School of Life Sciences, École Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9935-843X
  9. Bianca H Habermann

    Max Planck Institute of Biochemistry, Martinsried, Germany
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2457-7504
  10. Frank Schnorrer

    Muscle Dynamics, Aix Marseille University, CNRS, IDBM, Marseille, France
    For correspondence
    frank.schnorrer@univ-amu.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9518-7263

Funding

European Research Council ERC (FP/2007-2013)

  • Frank Schnorrer

Bettencourt Foundation

  • Frank Schnorrer

Turing Center for Living Systems

  • Frank Schnorrer

Max Planck Society

  • Frank Schnorrer

Centre National de la Recherche Scientifique

  • Frank Schnorrer

Aix-Marseille Université (ANR-11-IDEX-0001-02)

  • Frank Schnorrer

Agence Nationale de la Recherche (ANR-ACHN MUSCLE-FORCES)

  • Frank Schnorrer

Agence Nationale de la Recherche (ANR-18-CE45-0016-01)

  • Bianca H Habermann

Human Frontier Science Program (RGP0052/2018)

  • Frank Schnorrer

Agence Nationale de la Recherche (ANR-10-INBS-04-01)

  • Frank Schnorrer

Humboldt Foundation

  • Aynur Kaya-Çopur

EMBO

  • Aynur Kaya-Çopur

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Copyright

© 2021, Kaya-Çopur et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 3,179
    views
  • 478
    downloads
  • 36
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Aynur Kaya-Çopur
  2. Fabio Marchiano
  3. Marco Y Hein
  4. Daniel Alpern
  5. Julie Russeil
  6. Nuno Miguel Luis
  7. Matthias Mann
  8. Bart Deplancke
  9. Bianca H Habermann
  10. Frank Schnorrer
(2021)
The Hippo pathway controls myofibril assembly and muscle fiber growth by regulating sarcomeric gene expression
eLife 10:e63726.
https://doi.org/10.7554/eLife.63726

Share this article

https://doi.org/10.7554/eLife.63726

Further reading

    1. Developmental Biology
    Emily Delgouffe, Samuel Madureira Silva ... Ellen Goossens
    Research Article

    Although the impact of gender-affirming hormone therapy (GAHT) on spermatogenesis in trans women has already been studied, data on its precise effects on the testicular environment is poor. Therefore, this study aimed to characterize, through histological and transcriptomic analysis, the spermatogonial stem cell niche of 106 trans women who underwent standardized GAHT, comprising estrogens and cyproterone acetate. A partial dedifferentiation of Sertoli cells was observed, marked by the co-expression of androgen receptor and anti-Müllerian hormone which mirrors the situation in peripubertal boys. The Leydig cells also exhibited a distribution analogous to peripubertal tissue, accompanied by a reduced insulin-like factor 3 expression. Although most peritubular myoid cells expressed alpha-smooth muscle actin 2, the expression pattern was disturbed. Besides this, fibrosis was particularly evident in the tubular wall and the lumen was collapsing in most participants. A spermatogenic arrest was also observed in all participants. The transcriptomic profile of transgender tissue confirmed a loss of mature characteristics - a partial rejuvenation - of the spermatogonial stem cell niche and, in addition, detected inflammation processes occurring in the samples. The present study shows that GAHT changes the spermatogonial stem cell niche by partially rejuvenating the somatic cells and inducing fibrotic processes. These findings are important to further understand how estrogens and testosterone suppression affect the testis environment, and in the case of orchidectomized testes as medical waste material, their potential use in research.

    1. Developmental Biology
    2. Stem Cells and Regenerative Medicine
    Kara A Nelson, Kari F Lenhart ... Stephen DiNardo
    Research Article

    Niches are often found in specific positions in tissues relative to the stem cells they support. Consistency of niche position suggests that placement is important for niche function. However, the complexity of most niches has precluded a thorough understanding of how their proper placement is established. To address this, we investigated the formation of a genetically tractable niche, the Drosophila Posterior Signaling Center (PSC), the assembly of which had not been previously explored. This niche controls hematopoietic progenitors of the lymph gland (LG). PSC cells were previously shown to be specified laterally in the embryo, but ultimately reside dorsally, at the LG posterior. Here, using live-imaging, we show that PSC cells migrate as a tight collective and associate with multiple tissues during their trajectory to the LG posterior. We find that Slit emanating from two extrinsic sources, visceral mesoderm and cardioblasts, is required for the PSC to remain a collective, and for its attachment to cardioblasts during migration. Without proper Slit-Robo signaling, PSC cells disperse, form aberrant contacts, and ultimately fail to reach their stereotypical position near progenitors. Our work characterizes a novel example of niche formation and identifies an extrinsic signaling relay that controls precise niche positioning.