Abstract
ABSTRACTAnimal cells are thought to sense mechanical forces via the transcriptional co-activators YAP (or YAP1) and TAZ (or WWTR1), the sole Drosophila homolog of which is named Yorkie (Yki). In mammalian cells in culture, artificial mechanical forces induce nuclear translocation of YAP and TAZ. Here, we show that physiological mechanical strain can also drive nuclear localisation of Yki and activation of Yki target genes in the Drosophila follicular epithelium. Mechanical strain activates Yki by stretching the apical domain, reducing the concentration of apical Crumbs, Expanded, Kibra and Merlin, and reducing apical Hippo kinase dimerisation. Overexpressing Hippo kinase to induce ectopic activation in the cytoplasm is sufficient to prevent Yki nuclear localisation even in flattened follicle cells. Conversely, blocking Hippo signalling in warts clones causes Yki nuclear localisation even in columnar follicle cells. We find no evidence for involvement of other pathways, such as Src42A kinase, in regulation of Yki. Finally, our results in follicle cells appear generally applicable to other tissues, as nuclear translocation of Yki is also readily detectable in other flattened epithelial cells such as the peripodial epithelium of the wing imaginal disc, where it promotes cell flattening.
Highlights
The Hippo signalling pathway was discovered in Drosophila as being essential to restrict cell proliferation in growing tissues
Cortical Myosin II staining reveals the dramatic change in cell shape, but does not increase in intensity in stretch cells relative to columnar cells, suggesting that flattening involves a large increase in mechanical strain without a correspondingly large increase in mechanical stress (Fig. 1B)
As in the follicular epithelium, dilution of DISCUSSION Our results demonstrate that physiological mechanical strain forces are sensed via the canonical Hippo pathway in Drosophila epithelia
Summary
The Hippo signalling pathway was discovered in Drosophila as being essential to restrict cell proliferation in growing tissues (reviewed by Badouel et al, 2009b; Halder and Johnson, 2011; Harvey and Hariharan, 2012; Pan, 2010). The core Hippo (Hpo/ MST)-Warts (Wts/LATS) kinase cassette is activated by the Crumbs-Expanded (Crb-Ex) and Merlin-Kibra (Mer-Kib) protein complexes at apical cell-cell junctions (Badouel et al, 2009a; Baumgartner et al, 2010; Chen et al, 2010; Genevet et al, 2010; Hamaratoglu et al, 2006; Ling et al, 2010; Robinson et al, 2010; Su et al, 2017; Yu et al, 2010). Mutation of Wts, or mutation of multiple target serine residues in Yki (3SA) or YAP (5SA) is sufficient to induce nuclear translocation of Yki or YAP, which co-activates the DNA-binding transcription factor Scalloped/ TEAD to drive target gene expression (Dong et al, 2007; Huang et al, 2005; Oh and Irvine, 2008, 2009)
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