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

Abstract

Tissue morphogenesis requires the coordinated regulation of cellular behavior, which includes the orientation of cell division that defines the position of daughter cells in the tissue. Cell division orientation is instructed by biochemical and mechanical signals from the local tissue environment, but how those signals control mitotic spindle orientation is not fully understood. Here, we tested how mechanical tension across an epithelial monolayer is sensed to orient cell divisions. Tension across Madin-Darby canine kidney cell monolayers was increased by a low level of uniaxial stretch, which oriented cell divisions with the stretch axis irrespective of the orientation of the cell long axis. We demonstrate that stretch-induced division orientation required mechanotransduction through E-cadherin cell-cell adhesions. Increased tension on the E-cadherin complex promoted the junctional recruitment of the protein LGN, a core component of the spindle orientation machinery that binds the cytosolic tail of Ecadherin. Consequently, uniaxial stretch triggered a polarized cortical distribution of LGN. Selective disruption of trans engagement of E-cadherin in an otherwise cohesive cell monolayer, or loss of LGN expression, resulted in randomly oriented cell divisions in the presence of uniaxial stretch. Our findings indicate that E-cadherin plays a key role in sensing polarized tensile forces across the tissue and transducing this information to the spindle orientation machinery to align cell divisions.cell-cell adhesion | cell division orientation | mitotic spindle | mechanotransduction

Decoupling the roles of cell shape and mechanical stress in orienting and cueing epithelia mitosis

“…Contrary to observations in monolayers (Hart et al, 2017), we found that cells in stretched tissue divide according to cell shape both when θ J is oriented with (Figure 3A) and against (Figure 3B&C) the direction of stretch. Moreover, in the case of cells that are relatively round in shape (C J >0.65), there is no preference for aligning with the global stretch direction and indeed alignment with TCJ shape still appears more accurate than with the stretch axis (Figure S2A&B; p < 0.005 for TCJS, not significant for stretch direction, Mann-Whitney U test).…”

Generation of anisotropic strain dysregulates wild-type cell division at the interface between host and oncogenic tissue

“…Previous studies have shown that cell division in epithelia can increase in rate and acquire a directional bias following an externally imposed anisotropic mechanical strain, similar to what we see in host cells neighbouring a kRas V12 cluster [34,36,[92][93][94]. By analysing the orientation of a cell's long axis, we found that wild-type cells close to GFP-kRas V12 cell clusters demonstrated features consistent with the presence of anisotropic stress [95], that were absent in wild-type cells close to cMYC expressing clusters [35,[62][63][64][65].…”

A mechanosensitive RhoA pathway that protects epithelia against acute tensile stress

“…Furthermore, our experiments tested the effects of acute application of tensile stress. Other mechanisms can be elicited when stresses are applied more slowly or sustained longer, such as cellular rearrangements and oriented cell division (Hart, et al, 2017;Etournay, et al, 2015;Wyatt, et al, 2015;Campinho, et al, 2013). Lessey, E.C., Guilluy, C., and Burridge, K. (2012).…”