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

VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle
VGLL3 operates via TEAD1, TEAD3 and TEAD4 to influence myogenesis in skeletal muscle
Other Titles:
Journal of Cell Science
Publication Date:
05 July 2019
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, Henning Wackerhage Journal of Cell Science 2019 132: jcs225946 doi: 10.1242/jcs.225946 Published 5 July 2019
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.
License type:
Funding Info:
N.F. was initially funded by the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement number 262948-2 (BIODESIGN), and then supported by the King’s Health Partners R&D Challenge Fund (R151006) and the Medical Research Council (MR/P023215/1). A.D.M. was funded initially by Sarcoma UK (grant number SUK09.2015) and then supported by funding from Postdoctoral Fellowship Program (Helmholtz Center, Munich, Germany). C.S. was funded by MRC grant G11001931 to H.W. and P.S.Z., and then BIODESIGN. J.P. is in receipt of aWellcome Trust PhD Studentship (203949/Z/16/Z). O.J. was financed by the Biotechnology and Biological Sciences Research Council (BBSRC) (BB/L009943/1, awarded to S.D.R.H.). The Zammit laboratory was additionally supported by Association Française contre les Myopathies (17865). This research is also supported by the Agency for Science, Technology and Research (A*STAR), Singapore.
Files uploaded:

File Size Format Action
jcs225946full.pdf 9.43 MB PDF Open