E-cadherin clustering as a regulator of morphogenesis

Gerald Lerchbaumer, Sergio Simoes, Ermia Etemadi, Fadi Zidan, Gonca Erdemci-Tandogan, Ulrich Tepass

Posted on: 10 September 2026

Preprint posted on 22 April 2026

Hand in hand - E-cadherin with E-cadherin: The number of E-cadherin connections influences morphogenetic tissue movements.

Selected by Girish Kale, preLights peer support

Categories: cell biology, developmental biology

Written by: Chiara Hüttner (Bachelor student at the University of Hohenheim, Stuttgart. Germany)

Background:

During early development of animals, when epithelial tissue needs to move, there are many obstacles to overcome. One of these is maintaining structural cohesion at a time of tissue rearrangement. But how does the tissue achieve this?

For that, cells need to stay in contact and interact with one another. Something for which adherens junctions (AJ), composed of the cadherin-catenin complex (CCC), are essential. Cadherin links up with cadherins from neighbouring cells on the extracellular side, while on the intracellular side, catenins link up with the actomyosin cytoskeleton. This kind of connectivity also propagates the tension in the tissue. The generated tension causes a threshold, so-called ‘yield stress’. This is the barrier that epithelial tissue needs to overcome to start moving and rearranging.

In the preprint, the authors focus on E-cadherin, which can form cis- and trans-clusters with other E-cadherins and thereby influence cell adhesion. Because E-cadherin directly mediates cell-cell attachment, its mobility on the membrane and turnover may be important for regulating tissue movements. This study is the first to use optogenetic clustering as a gain-of-function tool. Using Drosophila embryos, the authors looked at different tissue movements to see whether E-cadherin clustering could influence morphogenesis. These movements included germband extension, neuroblast ingression, and mesoderm invagination.

Three morphogenetic movements (adapted from Figure 7 in the preprint)

Key findings:

LARIAT-introduced E-cadherin clustering:

The authors used the optogenetic method LARIAT to induce clustering of E-cadherin in Drosophila melanogaster embryos. In embryos expressing GFP-tagged E-cadherin and LARIAT, blue light activates the system by causing CRY2 (fused to a GFP-nanobody) to bind CIBN (fused to a multimerization domain). Because the nanobody binds GFP, this clusters endogenous GFP-tagged E-cadherins at the membrane. The authors looked at only CRY2-expressing genotypes to show the dose-dependent amount of clustering, caused by CRY2 oligomerization. As expected, E-cadherin showed an increase in junctional accumulation in the tissue.

LARIAT-mediated E-cadherin clustering (adapted from Figure 1 in the preprint)

LARIAT-induced E-cadherin clustering reduces E-cadherin mobility and turnover

Next, the authors photobleached areas within a junction or whole junctions in Drosophila embryonic tissue for Fluorescence Recovery After Photobleaching (FRAP) analysis. The increased clustering due to LARIAT caused a reduction in E-cadherin mobility and turnover, shown by a lower recovery rate using the FRAP method. The authors compared this condition with E-cadherin overexpression (Ecad-OE). Ecad-OE also caused an increase in E-cadherin on the cell membrane, but this did not last for long, as E-cadherin was removed again through endocytosis. So, the authors concluded that E-Cadherin clustering via LARIAT is distinct from mere Ecad-OE and could be used to investigate the influence of increased adhesion strength.

E-cadherin clustering affects other CCC components

To look at whether clustering also influences the levels of the other components of the CCC, the authors used live imaging of embryos and antibody staining in fixed embryos. More α-catenin and β-catenin were detected as a result of E-cadherin clustering via LARIAT. This suggests that the generated CCCs build functional adherens junctions. Because the adhesion strength is higher after clustering, the authors also assumed that there could be more actomyosin. They thus quantified myosin flow with Particle image velocimetry (PIV), but the results showed that there is no change in the amount of actin and myosin. So, the adhesion strength does not depend on actomyosin.

Increased E-cadherin clusters influence certain morphogenetic movements

The clustering of E-cadherin reduced cell intercalation and convergent extension. This is presumably because of the different distribution of adherens junctions on the horizontal and vertical junctions. These appeared more uniform, leading to the loss of planar polarity. The myosin contractility mechanism could not overcome the higher yield stress, and the germband of the embryo failed to fully extend.

The other two morphogenetic movements, mesoderm invagination and neuroblast ingression, showed different outcomes after E-cadherin clustering, in line with the authors’ expectations. Neuroblast ingression was delayed due to the lack of E-cadherin mobility and turnover, which reduced the junctional remodelling and removal of the apical membrane. In mesoderm invagination, this had no effect, as the monolayer invaginated with just a little cell neighbour exchange, meaning the yield stresses do not play a role here.

In conclusion, E-cadherin clustering reduces the mobility and turnover of E-cadherins; the adhesion strength increases, and so does the tissue’s friction, due to which junction removal and rebuilding are severely affected. Because this is needed for cell rearrangements, morphogenetic tissue movements like germband extension and neuroblast ingression fail after E-cadherin clustering.

E-cadherin clustering ↑ ➡ mobility ↓ ➡ friction ↑ ➡ cell rearrangement ↓

Why I highlight this preprint:

For my bachelor’s thesis, I am looking at evolutionary changes in mesoderm internalization. In Drosophila melanogaster, during mesoderm invagination, the tissue moves as a monolayer epithelium inward without cell neighbour exchange. In contrast, in the midge, Chironomus riparius, the mesoderm cells undergo cell ingression along with neighbour exchange (showing similarity with neuroblast ingression in Drosophila). That is why the results of the different effects of E-cadherin clustering on cell ingression and cell invagination are particularly interesting to me. This may be a reason for an evolutionary change of the mechanism of how the mesoderm moves inwards: From cell ingression to monolayer invagination. This made me wonder whether cell-cell adhesion might differ between these species, and whether a distinct regulation of E-cadherin clustering might dictate the evolutionary divergence.

Questions to the authors:

In the manuscript, you have shown two examples of E-cadherin clustering: a passive one, exploiting the dimerization of CRY2; and an actively tuneable one, using the LARIAT system. I am wondering: could the amount of E-cadherin clustering be controlled exactly, either using this or another system, so as to achieve a specific adhesion strength? Tunability such as this could be useful to further test the exact transition where adhesion strength overpowers actomyosin forces to block intercalation.
What will happen if an increase in actomyosin is induced in addition to E-cadherin clustering? Do you think that the current vertex models are sophisticated enough to come up with a testable prediction? If not, which other factors should be looked at next to improve the vertex model?

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