E‐cadherin mediates apical membrane initiation site localisation duringde novopolarisation of epithelial cavities

Abstract

Individual cells within de novo polarising tubes and cavities must integrate their forming apical domains into a centralised apical membrane initiation site (AMIS). This is necessary to enable organised lumen formation within multi-cellular tissue. Despite the well-documented importance of cell division in localising the AMIS, we have found a division-independent mechanism of AMIS localisation that relies instead on Cadherin-mediated cell-cell adhesion. Our study of de novo polarising mouse embryonic stem cells (mESCs) cultured in 3D suggests that cell-cell adhesion localises apical proteins such as PAR-6 to a centralised AMIS. Unexpectedly, we also found that mESC clusters lacking functional E-cadherin still formed a lumen-like cavity in the absence of AMIS localisation but did so at a later stage of development via a "closure" mechanism, instead of via hollowing. This work suggests that there are two, interrelated mechanisms of apical polarity localisation: cell adhesion and cell division. Alignment of these mechanisms in space allows for redundancy in the system and ensures the development of a coherent epithelial structure within a growing organ.

Cleavage furrow-directed cortical flows bias mechanochemical pathways for PAR polarization in theC. elegansgerm lineage

“…One striking example is the so-called mirror symmetric division, in which two daughter cells polarize in opposing directions relative to the nascent cell contact (Buckley et al, 2013; Tawk et al, 2007). Roles for the spindle midzone, midbody remnants and cell contact have been reported (Buckley et al, 2013; Li et al, 2014; Liang et al, 2022; Luján et al, 2016; Schlüter et al, 2009; Wang et al, 2014), which likely play complementary roles during establishment of cell and tissue polarity (Buckley and St Johnston, 2022). However, whether advection of polarity proteins by furrow-directed flows also plays a role has not been explicitly tested.…”

“…This division-linked polarity has been linked to a variety of spatial cues, including cytokinesis remnants, the spindle midzone, the midbody, and/or contact-dependent signaling between newly generated daughters (Etienne-Manneville, 2004; Harris and Tepass, 2010; Li et al, 2014; Luján et al, 2016; Meitinger et al, 2014; Miller et al, 2020; Pollarolo et al, 2011; Rathbun et al, 2020; Schlüter et al, 2009; Wang et al, 2014), which likely act together to ensure proper cell polarization (Buckley and St Johnston, 2022). In many of these cases polarization has been linked to the accumulation of polarity related molecules, including PAR-3, within the cleavage furrow and/or nascent contact site (Buckley et al, 2013; Harris and Peifer, 2004; Liang et al, 2022; Tawk et al, 2007). Our data further suggests that advection of polarity proteins by furrow-directed cortical flow also may play a role, by providing a simple mechanism to concentrate such molecules within the furrow to ensure tight coupling between division and the polarity axis.…”

Cadherin‐mediated adhesion takes control

“…More interestingly, these division‐blocked cells also properly localised AMIS markers (Par3 and ZO‐1) at the centre of the cell–cell contacts at the incipient lumen (Fig 1A). These results suggest a division‐independent mechanism of AMIS localisation that should depend instead on different polarity determinants (Liang et al , 2022).…”

“…Previous work had shown that despite the well‐documented importance of cell division in localising the AMIS (Buckley & St Johnston, 2022), a division‐independent mechanism of AMIS localisation in zebrafish neural primordium relies instead on cadherin‐mediated cell adhesion (Buckley et al , 2013). Now, Liang et al (2022) have analysed the importance of cell adhesion in mammals. Using the mouse embryonic stem cell (mESC) culture in Matrigel, an in vitro model for the de novo polarisation of the mouse epiblast (Shahbazi, 2020; Kim & Bedzhov, 2022), Liang et al asked whether division‐independent polarisation is a conserved feature of de novo lumenogenesis.…”

“…These structures present polarised Golgi apparatus, apically localised podocalyxin and apico‐laterally localised junctional PAR‐3 and ZO‐1. Figure modified from Liang et al (2022).…”