Abstract
How the behaviour of somatic stem cells (SCs) is influenced by mechanical signals remains a black-box in cell biology. Here we show that YAP/TAZ regulation by cell shape and rigidity of the extracellular matrix (ECM) dictates a pivotal SC decision: to remain undifferentiated and grow, or to activate a terminal differentiation programme. Notably, mechano-activation of YAP/TAZ promotes epidermal stemness by inhibition of Notch signalling, a key factor for epidermal differentiation. Conversely, YAP/TAZ inhibition by low mechanical forces induces Notch signalling and loss of SC traits. As such, mechano-dependent regulation of YAP/TAZ reflects into mechano-dependent regulation of Notch signalling. Mechanistically, at least in part, this is mediated by YAP/TAZ binding to distant enhancers activating the expression of Delta-like ligands, serving as 'in cis' inhibitors of Notch. Thus YAP/TAZ mechanotransduction integrates with cell-cell communication pathways for fine-grained orchestration of SC decisions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actins / metabolism
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Cell Cycle Proteins
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Cell Differentiation
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Cell Lineage*
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Cell Shape
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Epidermal Cells*
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Epistasis, Genetic
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Extracellular Matrix / metabolism
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Humans
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Infant, Newborn
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Intracellular Signaling Peptides and Proteins / metabolism*
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Male
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Mechanotransduction, Cellular
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Mice, Transgenic
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Models, Biological
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Phosphoproteins / metabolism*
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Receptors, Notch / metabolism*
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Reproducibility of Results
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Signal Transduction
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Stem Cells / cytology*
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Stem Cells / metabolism
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Trans-Activators
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Transcription Factors
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Transcription, Genetic
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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YAP-Signaling Proteins
Substances
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Actins
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Adaptor Proteins, Signal Transducing
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Cell Cycle Proteins
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Intracellular Signaling Peptides and Proteins
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Phosphoproteins
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Receptors, Notch
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Trans-Activators
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Transcription Factors
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Transcriptional Coactivator with PDZ-Binding Motif Proteins
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WWTR1 protein, human
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Wwtr1 protein, mouse
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YAP-Signaling Proteins
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YAP1 protein, human
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Yap1 protein, mouse