Skeletal muscle has regeneration ability due to the existence of muscle satellite cells (MuSCs). MuSCs are adult stem cells that regenerate skeletal muscles in response to muscle injury. MuSCs undergo cell proliferation and differentiation to achieve timely regeneration. MyoD is considered to be the master regulator of myogenesis, which directly activates the transcription of MyoG for terminal differentiation.
VGLL4, a new member of the Hippo pathway, is intensively investigated in inhibition of cell proliferation by competing with YAP to bind TEADs. The researchers identify that VGLL4 exhibits opposing effects on TEAD4 mediated transcription in YAP dependent and independent manners at different stages of muscle regeneration, thereby coordinating the balance between MuSCs proliferation and differentiation. MuSCs-specific VGLL4 knockout mice display increased MuSCs proliferation and impaired MuSCs differentiation, ultimately resulting in muscle regeneration defects.
Mechanistically, at the proliferation stage of muscle regeneration, VGLL4 functions as a conventional YAP repressor to inhibit MuSCs proliferation. At the late stage of muscle regeneration, VGLL4 acts as an indispensable co-activator of TEAD4 to regulate MyoG transcription and the YAP-independent function plays critical roles in facilitating the initiation of muscle satellite cell differentiation. Moreover, VGLL4 could stabilize the protein-protein interaction between MyoD and TEAD4 to achieve efficient MyoG transactivation. These findings define the dual roles of VGLL4 in regulating muscle regeneration at different stages, which may open novel therapeutic perspectives for muscle regeneration.
This study entitled as “Dual function of VGLL4 in muscle regeneration” was published in EMBO J on July 22, 2019.
FENG Xue, WANG Zuoyun, WANG Fei and their colleagues from the research group led by Prof. ZHANG Lei and Prof. HU Ping completed this work. The work was financially supported by the National Key Research and Development Program of China, National Natural Science Foundation of China, “Strategic Priority Research Program” of Chinese Academy of Sciences, Shanghai Program, NN-CAS Foundation, Science and Technology Commission of Shanghai Municipality, Youth Innovation Promotion Association of the Chinese Academy of Sciences and China Postdoctoral Science Foundation.
Working model
Contact: rayzhang@sibcb.ac.cn; hup@sibcb.ac.cn.
Reference: https://www.embopress.org/doi/abs/10.15252/embj.2018101051
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