⑵Notch signaling pathway
Notch signaling is frequently involved in development and homeostasis in
multiple tissues, resulting in diverse cellular responses, and Notch
activity regulates growth, differentiation, survival, and stem cell
behavior in a highly context-dependent manner[51,52]. Notch controls binary cell fate during
morphogenesis, whereas YAP/TAZ translates the physical properties of the
microenvironment into key cellular decisions [53].
Notch and YAP-TEAD drive the specification of trophectoderm fate
downstream of cell polarity by activating the expression of the
trophectoderm-specific gene Cdx2 in combination with
trophectoderm-specific enhancers [54]. YAP/TAZ can
act upstream of Notch signaling by activating Notch receptors[53]. For example, during postinflammatory
intestinal repair, the Notch signaling pathway is downstream of YAP/TAZ
activation [3]. YAP/TAZ is activated in tip cells
through actomyosin tension-mediated GPCR signaling, LPA4 and LPA6 during
angiogenesis. YAP/TAZ controls
neovascularization by blocking β-catenin-NICD-mediated expression of the
Notch ligand Dll4 [55]. In the corneal epithelium,
Notch deletion triggers inflammatory cytokine secretion and continues
the cycle of injury and repair [56,57]. This
persistent inflammation causes ECM deposition and fibrosis, leading to
activation of YAP/TAZ mechanotransduction [58].
Both in vitro and in vivo experiments have shown that low cell density
or high ECM rigidity can trigger the activation of YAP/TAZ-TEAD in basal
progenitor cells to maintain them via inhibiting Notch signaling[59]. In basal progenitors, the
YAP/TAZ-TEAD complex activates the
transcription of Dll1 and Dll3; then, cis-interaction of Dll1 and Dll3
with Notch receptors can block Notch activation, thereby preventing
epidermal differentiation [59].