Signal integration in muscle stem cells during tissue regeneration: Dissecting Notch signaling in quiescent and activated muscle stem cells

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Stem cells maintain tissues and repair tissue injuries. They remain quiescent when they are not needed, but they can be activated for regeneration upon demand. Thus, by responding to environmental cues, they shuttle between quiescent and activated states. Dissecting the mechanisms that regulate the transition between quiescence and activation is critical for understanding tissue maintenance and repair, but also for the manipulation of stem cells in the context of regenerative medicine. The adult skeletal muscle tissue has an extraordinary capacity to regenerate after injury. Muscle stem cells (MuSCs) are the cellular source for repair and reside in a specialized microenvironment called the niche. Our Consortium showed previously that Notch signaling is critical for two distinct and seemingly contradictory processes that depend on the state of MuSCs, first the maintenance of the quiescent state of MuSCs, which requires the construction of their niche, and second the suppression of differentiation of activated MuSCs that ensures that they can proliferate and self-renew. Our planned experiments combine mouse genetic models with high-throughput proteomics to decipher the mechanisms by which Notch signaling regulates quiescence and activation of MuSCs. To date, the majority of analyses on MuSC quiescence and self-renewal are based on transcriptomics as a convenient proxy of the proteome, and use transcriptomics to infer lineage identity, active biochemical pathways and cellular functions. However, protein interactions and reversible posttranslational modifications are sensors that modulate entire cellular pathways and adopt them to changing conditions. We hypothesize that the diverse roles of Notch reflect the outcome of crosstalk with other signaling pathways, which determines its interacting partners, their posttranslational modifications and the dynamics of signaling propagation. Therefore, in this Consortium, we will apply cutting edge proteomic methodologies combined with mouse genetics to provide a comprehensive study on signal integration and Notch signaling in quiescent and activated MuSCs.