YAP/TAZ link cell mechanics to Notch signalling to control epidermal stem cell fate

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.

Bile canaliculi remodeling activates YAP via the actin cytoskeleton during liver regeneration

“…Cytochalasin D, latrunculin A, and SMIFH2 induced nuclear YAP translocation ( Fig 5E), mimicking the effect of DCA, whereas the other drugs were either ineffective or inhibitory (Y27). The effects of cytochalasin D and latrunculin A in hepatocytes are in contrast to other previously reported systems (Dupont et al, 2011;Totaro et al, 2017). To verify the in/activation of YAP by the actin inhibitors, we inspected the expression of some target genes (Cyr61, CTGF, Ankrd1) by qPCR (Appendix Fig S7D).…”

“…To test whether YAP can sense BC network alterations, we examined its spatio‐temporal dynamics using a specific antibody, validated by loss of signal upon YAP KO (Appendix Fig S3). We correlated YAP nuclear localization, as readout for its activity (Yagi et al , ; Zhao et al , ), with hepatocyte proliferation, detected by the cell cycle marker PCNA, as indicator for the onset of the cellular regenerative response. To account for previously reported spatial heterogeneities of proliferation within the liver lobule (Wu et al , ), we imaged the entire CV‐PV axis at 17 time points (0.5–7 days) during regeneration (Fig A and B) and upon sham surgery (Appendix Fig S4A and B).…”

Excitable Dynamics and Yap-Dependent Mechanical Cues Drive the Segmentation Clock

“…when the system is above the excitability threshold as when lowering Yap signaling for instance), Notch signaling would only be needed to synchronize oscillators. These effects might result in part from Yap interacting with Notch signaling as demonstrated in other systems (Manderfield et al, 2015; Totaro et al, 2017). Since the cyclic activity induced by LatA treatment was observed independently of γ-secretase activity, it raises the question of the pacemaker controlling Lfng oscillations, as this gene is considered a direct Notch target (Morales et al, 2002).…”

Hippo‐Yap/Taz signaling: Complex network interactions and impact in epithelial cell behavior

“…In epidermal basal cells, Hippo‐mediated mechanotransduction accumulates Yap in the nucleus and induces Notch ligand Delta‐like 1 ( Dll1 ). Yap‐induced Dll1 prevents these cells from expressing Notch , but activates Notch signaling in neighbor cells to induce their differentiation (Totaro et al, ). This mechanism was also demonstrated in intestinal organoids, wherein cells have different levels of nuclear Yap.…”