VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle

Nicolas Figeac, Abdalla D. Mohamed, Congshan Sun, Martin Schönfelder, David Matallanas, Amaya Garcia-Munoz, Edoardo Missiaglia, Elaina Collie-Duguid, Vanessa De Mello, Ajaybabu V. Pobbati, Johanna Pruller, Oihane Jaka, Stephen D. R. Harridge, Wanjin Hong, Janet Shipley, Neil Vargesson, Peter S. Zammit (Corresponding Author), Henning Wackerhage (Corresponding Author)

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Abstract

VGLL proteins are transcriptional co-factors that bind TEAD family transcription factors to regulate events ranging from wing development in fly, to muscle fibre composition and immune function in mice. Here, we characterise Vgll3 in skeletal muscle. Vgll3 is expressed at low levels in healthy muscle but levels increase during hypertrophy or regeneration, and in disease, VGLL3 is highly expressed in dystrophic muscle and alveolar rhabdomyosarcoma. Interaction proteomics revealed that VGLL3 binds TEAD1,3,4 in myoblasts and/or myotubes. However, there is no interaction with proteins of major regulatory systems such as the Hippo kinase cascade, unlike the TEAD cofactors YAP and TAZ. Vgll3 overexpression reduces the Hippo negative feedback loop, affecting expression of muscle-regulating genes including Myf5, Pitx2/3, Wnts and IGFBP. Vgll3 mainly represses gene expression, regulating similar genes to that of YAP1 and TAZ. SiRNA-mediated Vgll3 knockdown suppresses myoblast proliferation, while Vgll3 overexpression strongly promotes myogenic differentiation. Skeletal muscle is overtly normal in Vgll3-null mice though, presumably due to feedback signalling and/or redundancy. This work identifies Vgll3 as a transcriptional cofactor operating with the Hippo signal transduction network to control myogenesis.
Original languageEnglish
Article numberjcs225946
JournalJournal of Cell Science
Volume132
Early online date28 May 2019
DOIs
Publication statusPublished - 5 Jul 2019

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Keywords

  • Vgll
  • Yap
  • Taz
  • Skeletal muscle
  • stem cells
  • WWTR1
  • TEAD
  • Stem cells
  • YAP
  • TAZ
  • VGLL3
  • TRANSCRIPTION FACTORS
  • PROTEIN
  • RHABDOMYOSARCOMA REVEALS
  • VESTIGIAL-LIKE
  • TISSUE
  • EFFECTOR
  • GENE-EXPRESSION
  • COFACTOR
  • BINDING

ASJC Scopus subject areas

  • Cell Biology

Cite this

Figeac, N., Mohamed, A. D., Sun, C., Schönfelder, M., Matallanas, D., Garcia-Munoz, A., ... Wackerhage, H. (2019). VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle. Journal of Cell Science, 132, [jcs225946 ]. https://doi.org/10.1242/jcs.225946