Cell division orientation is coupled to cell–cell adhesion by the E-cadherin/LGN complex

Abstract

Both cell–cell adhesion and oriented cell division play prominent roles in establishing tissue architecture, but it is unclear how they might be coordinated. Here, we demonstrate that the cell–cell adhesion protein E-cadherin functions as an instructive cue for cell division orientation. This is mediated by the evolutionarily conserved LGN/NuMA complex, which regulates cortical attachments of astral spindle microtubules. We show that LGN, which adopts a three-dimensional structure similar to cadherin-bound catenins, binds directly to the E-cadherin cytosolic tail and thereby localizes at cell–cell adhesions. On mitotic entry, NuMA is released from the nucleus and competes LGN from E-cadherin to locally form the LGN/NuMA complex. This mediates the stabilization of cortical associations of astral microtubules at cell–cell adhesions to orient the mitotic spindle. Our results show how E-cadherin instructs the assembly of the LGN/NuMA complex at cell–cell contacts, and define a mechanism that couples cell division orientation to intercellular adhesion.

E-cadherin and LGN align epithelial cell divisions with tissue tension independently of cell shape

“…We showed previously that LGN binds the cytosolic tail of E-cadherin to stabilize cortical astral microtubule interactions at E-cadherin adhesions and establish planar epithelial divisions (8). Strikingly, we observed that the junctional recruitment of LGN was dependent on cell density:…”

“…The cell-cell adhesion protein E-cadherin has a prominent role in orienting cell divisions (8,(26)(27)(28)(29)(30) as well as in sensing tensile forces between neighboring cells (31,32). Tension on E-cadherin junctions can be generated by forces exerted on the extracellular domain by neighboring cells, which can be induced by application of external stretch, and intracellularly through actomyosin contraction (31).…”

“…This evolutionarily conserved adaptor protein orients the mitotic spindle by providing cortical anchorage sites for astral microtubules of the spindle and applying a pulling force on those microtubules through the associated proteins NuMA and dynein (7). Recently, we showed that LGN is recruited to E-cadherin-based cell-cell contacts during interphase (8). E-cadherin couples neighboring cells to each other through homotypic interactions of its extracellular domain, and associates with the actin cytoskeleton through catenin proteins bound to its cytosolic tail (9).…”

“…E-cadherin couples neighboring cells to each other through homotypic interactions of its extracellular domain, and associates with the actin cytoskeleton through catenin proteins bound to its cytosolic tail (9). LGN adopts a 3D structure similar to the cadherin-bound catenins, and is recruited to cell-cell junctions by direct binding to the cytosolic tail of E-cadherin to ensure epithelial cells divide within the plane of the epithelium (8).…”

Spindle orientation: a question of complex positioning

“…A very recent report (Gloerich et al, 2017) demonstrates that another adherens junction protein, E-cadherin, can also bind directly to LGN. Using a clever cultured cell system, this study shows that E-cadherin recruits LGN to cell-cell contacts and can serve as an instructive cue for spindle orientation.…”