Mechanosensitive binding of p120-Catenin at cell junctions regulates E-Cadherin turnover and epithelial viscoelasticity
Posted on: 23 July 2018 , updated on: 24 July 2018
Preprint posted on 27 June 2018
Tissue viscoelasticity as a readout of tissue tension: mechanosensitive p120-Catenin regulates E-cadherin turnover at cellular junctions.
Selected by Ivana Viktorinová
Categories: biophysics, cell biology, developmental biology
Background and summary
How tissues form remains a key open question in developmental biology. During animal development, tissues undergo dynamic reorganization that involves the coordinated behavior of cells including collective cell migration, cell rearrangements, cell shape/size changes and cell divisions/death. In the last decade, the field of developmental biology has been truly revolutionized by biophysical approaches that have revealed mechanical force (stress) in developing tissues. Therefore, to obtain a comprehensive picture of all developmental processes, it is essential to understand how genetic mechanisms and tissue mechanics work together.
Although most studies have focused on the generation of mechanical stress organized by biochemical signals (e.g. Heisenberg and Ballaïche, 2013), relatively little is known regarding how animal tissues actually respond to such stress (Chanet and Martin, 2014). A recent preprint by Iyer et al. provides a novel insights on the latter through the study of the developing Drosophila pupal wing. The authors show that the wing epithelium can be seen as a soft material with viscoelastic properties. This means that after mechanical stress has been applied to the wing tissue, the tissue does not reorganize instantly but instead with a delay (several hours in this case) and in irreversible manner. The authors also hypothesize and experimentally test whether mechanical stress influences the viscoelastic character/deformation of the wing epithelium at the molecular level. This preprint extends our knowledge about tissue deformation principles known from Drosophila embryonic germband extension (Rauzi et al. 2010).
Key findings
First, using circular and linear laser ablations, the authors find that the mechanical stress detected increases during hinge contraction in the developing wing at 20hAPF. This then gradually decreases and is followed six hours later by cell elongation along the proximal-distal (PD) axis of the pupal wing. Based on this, the authors conclude that the wing epithelium has viscoelastic properties. Importantly, their experiments convincingly show that mechanical stress is linked to cell elongation in the developing wing epithelium. Therefore, they propose that not only cell rearrangements, but also cell shape changes/cell elongations contribute to viscoelastic stress relaxation in this tissue.
Second, inspired by studies in cell cultures, the authors hypothesize whether applied stress can destabilize the core component of adherens junctions, E-cadherin. They wonder whether this mechanism could be the missing response to mechanical stress in the developing Drosophila wing. Using fluorescence recovery after photobleaching (FRAP) and genetic approaches, the authors find a portion of E-cadherin turnover that positively correlates with the timing of mechanical stress during hinge contraction in wild-type and also in mutant situations (dumpy mutant/RNAi, where mechanical stress is impaired). These findings lead the authors to suspect that mechanical stress may regulate E-cadherin turnover and specifically its destabilization from adherens junctions.
Third, using a combination of FRAP and laser ablations, the authors show that, unlike lateral diffusion, membrane trafficking significantly contributes to the stress-dependent portion of E-cadherin recovery. Using the temperature-sensitive Dynamin mutant shibirets, they also find that this membrane trafficking fraction of E-cadherin recovery derives from endocytosis.
So what controls E-cadherin destabilization from the cellular membrane during endocytosis? Inspired by other studies, the authors investigate the role of p120-Catenin, which is known to bind to the juxta-membrane domain of E-cadherin in other tissues/cells. The authors find that p120-Catenin is released from the membrane upon high mechanical stress and leads to E-cadherin destabilization from adherens junctions. This is lost in dumpy mutants, where p120 shows preferential junctional localization. Thus, the authors conclude that p120-Catenin is mechanosensitive.
Figure 7: Proposed model for regulation of tissue viscoelasticity by mechanosensitive binding of p120.
The authors wrap up the whole story by showing that in double mutants (dumpy and p120308) E-cadherin turnover is rescued to a comparable wild-type level, although the mechanical stress level does remain low. On the other hand, the single p120 mutant shows constantly elevated levels of mechanical stress after its peak during later wing development and it also reflected in early cell elongation (already 1h after mechanical stress normally increases). Therefore, the authors summarize that p120-Catenin is not only mechanosensitive and regulates E-cad turnover through endocytosis, but also defines the epithelial viscoelasticity of this tissue.
What I like about it
In this preprint, the authors combine non-invasive and elegant genetic (classical, temperature sensitive mutants, RNAi) experiments with sophisticated invasive physical approaches (circular/linear laser ablations and FRAP). As a researcher working with Drosophila myself, I am impressed by the combination of methods used in this preprint. I especially appreciate the hidden hard work behind laser ablations and FRAP experiments along with their subsequent analyses that are always time-consuming. Overall, the authors present their data very well and clearly lead the reader through their whole story. I also like that this work nicely shows how collaborations at the interface between biology and physics field can provide beautiful novel insights. An additional advantage is that the conclusions drawn here in this preprint open the possibility to apply this knowledge to other animal tissues.
Future directions and questions for the authors
The quality of this work is superb with strikingly beautiful clear figures and I have only a few questions for the authors:
- The authors propose that the analyzed tissue has viscoelastic properties. I wonder how the authors conclude that the 6h delay between mechanical stress and cell elongation/tissue deformation is an intermediate shift that is typical for viscoelastic materials? I can see mechanical stress peaks and declines, but has no oscillations to test a phase shift between stress and tissue response.
- The authors show a positive correlation between mechanical stress and E-cadherin internalization. Nevertheless, is it possible to perform a direct experiment (e.g. with optical tweezers) where mechanical stress is artificially/ectopically increased in the pupal wing to see whether it leads to an increase in E-cadherin internalization/p120-Catenin cytoplasmatic localization?
- On a similar note, cell proliferations/cell divisions are active until 22.5h pAPF in the investigated area of the pupal wing (Etournay et al. 2015). Have the authors thought that this mechanism could underlie E-cadherin turnover/its internalization to remodel adherens junctions?
- If mechanical stress leads to delayed cell elongation/cell rearrangements/tissue deformation through the p120-Catenin/E-cadherin complex and actomyosin regulation in the pupal wing, what could be the source of initial mechanical stress?
References
Chanet, S., and Martin, A.C. (2014). Mechanical force sensing in tissues. Prog Mol Biol Transl Sci 126, 317-352.
Etournay, R., Popovic, M., Merkel, M., Nandi, A., Blasse, C., Aigouy, B., Brandl, H., Myers, G., Salbreux, G., Julicher, F., et al. (2015). Interplay of cell dynamics and epithelial tension during morphogenesis of the Drosophila pupal wing. Elife 4, e07090.
Heisenberg, C.P., and Bellaiche, Y. (2013). Forces in tissue morphogenesis and patterning. Cell 153, 948-962.
Rauzi, M., Lenne, P.F., and Lecuit, T. (2010). Planar polarized actomyosin contractile flows control epithelial junction remodelling. Nature 468, 1110-1114.
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