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Vgll3 operates via Tead1, Tead3 and Tead4 to influence myogenesis in skeletal muscle

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Nicolas Figeac, Abdalla Mohamed, Congshan Sun, Martin Schonfelder, David Matallanas, Amaya Garcia-Munoz, Edoardo Missiaglia, Elaina Collie-Duguid, Vanessa De Mello, Ajaybabu Pobbati, Johanna Prueller, Oihane Jaka Irizar, Stephen David Royston Harridge, Wanjin Hong, Janet Shipley, Neil Vargesson, Peter Steven Zammit, Henning Wackerhage

Original languageEnglish
Article number225946
JournalJournal of Cell Science
Volume132
Issue number13
Early online date5 Jul 2019
DOIs
Accepted/In press3 May 2019
E-pub ahead of print5 Jul 2019
Published5 Jul 2019

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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. We found that mouse Vgll3 was expressed at low levels in healthy muscle but that its levels increased during hypertrophy or regeneration; in humans, VGLL3 was highly expressed in tissues from patients with various muscle diseases, such as in dystrophic muscle and alveolar rhabdomyosarcoma. Interaction proteomics revealed that VGLL3 bound TEAD1, TEAD3 and TEAD4 in myoblasts and/or myotubes. However, there was no interaction with proteins from major regulatory systems such as the Hippo kinase cascade, unlike what is found for the TEAD co-factors YAP (encoded by YAP1) and TAZ (encoded by WWTR1). Vgll3 overexpression reduced the activity of the Hippo negative-feedback loop, affecting expression of muscle-regulating genes including Myf5, Pitx2 and Pitx3, and genes encoding certain Wnts and IGFBPs. VGLL3 mainly repressed gene expression, regulating similar genes to those regulated by YAP and TAZ. siRNA-mediated Vgll3 knockdown suppressed myoblast proliferation, whereas Vgll3 overexpression strongly promoted myogenic differentiation. However, skeletal muscle was overtly normal in Vgll3-null mice, presumably due to feedback signalling and/or redundancy. This work identifies VGLL3 as a transcriptional co-factor operating with the Hippo signal transduction network to control myogenesis.

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