Regulation of muscle stem cell function by Mpp7, Amot, Yap and Taz

Coordinating mechanical sensing and transcription activation is essential for muscle stem cell (MuSC) function during muscle regeneration. Here we report that MPP7, localized at the apical side of quiescent MuSCs, is an important regulator in MuSC activation, including proliferation and self-renewal. Mechanistically, MPP7 translocates to cell nucleus in response to the change of actin polymerization state with its binding partner AMOT (an actin binding protein) upon MuSC activation and acts to enhance the transcription activity of YAP and TAZ in the MuSC. RNA-seq of MuSCs isolated from control (Con), Mpp7 conditional knockout (cKO), Amot cKO, and Yap and Taz double cKO (YapTaz cKO) after 48 hrs in culture (for activation) in 2 replicas was used to determine the downtream genes regulated by Mpp7, Amot, Yap and Taz. Carm1 was one of the commonly shared down-regulated genes in all 3 cKOs and has been shown to be critical for MuSC self-renewal. We further demonstrated that the MPP7-PDZ domain interacts with TAZ indirectly via AMOT, and the MPP7-L27 domain cooperates with TAZ and another trsncription factor YY1 to regulate a select set of donwstream genes, including Carm1, for MuSC proliferation and self-renewal. Our data identified a coordinated molecular network from mechanical sensing to transcription regulation for MuSC function during muscle regeneration. Overall design: To investigate the relationship of MPP7/AMOT/YAP and TAZ in regulating satellite cell (SC) activation, Mpp7 cKO, Amot cKO and YapTaz cKO mice were generated and SCs from the mice were sorted and cultured to activate SCs. Gene expression profiling analysis was then performed using RNA seq data from control and conditional knockout SCs at 48 hrs after culture. Cross comparison of differentially expressed genes from RNA seq for control and Mpp7 cKO, Amot cKO and YapTaz cKO SCs