Trans-endocytosis of Planar Cell Polarity Complexes during Cell Division

Abstract

SUMMARY To coordinate epithelial architecture with proliferation, cell polarity proteins undergo extensive remodeling during cell division [1–3]. A dramatic example of polarity remodeling occurs in proliferative basal cells of mammalian epidermis whereupon cell division, transmembrane planar cell polarity (PCP) proteins are removed from the cell surface via bulk endocytosis [4]. PCP proteins form intercellular complexes, linked by Celsr1-mediated homophilic adhesion, that coordinate polarity non-autonomously between cells [5, 6]. Thus, the mitotic reorganization of PCP proteins must alter not only proteins intrinsic to the dividing cell, but also their interacting partners on neighboring cells. Here we show that intercellular Celsr1 complexes that connect dividing cells with their neighbors remain intact during mitotic internalization, resulting in uptake of Celsr1 protein from interphase neighbors. Trans-internalized Celsr1 carries with it additional core PCP proteins, including the posteriorly-enriched Fz6 and anteriorly-enriched Vangl2. Cadherin-mediated homophilic adhesion is necessary for trans-endocytosis, and adhesive junctional PCP complexes appear to be destined for degradation upon internalization. Surprisingly, whereas Fz6 and Vangl2 both internalize in trans, Vangl2 proteins intrinsic to the dividing cell remain associated with the plasma membrane. Persistent Vangl2 stabilizes Celsr1 and impedes its internalization, suggesting dissociation of Vangl2 from Celsr1 is a prerequisite for Celsr1 endocytosis. These results demonstrate an unexpected transfer of PCP complexes between neighbors, and suggest that the Vangl2 population that persists at the membrane during cell division could serve as an internal cue for establishing PCP in new daughter cells.

Endocytosis in proliferating, quiescent and terminally differentiated cells

“…In the absence of its typical cargos, residual CME during mitosis is dedicated to the internalization of specific receptors, namely the receptor for the TGF-β receptor-type morphogen decapentaplegic (Dpp), fibroblast growth factor receptor (FGFR), the Notch receptor, and the planar cell polarity (PCP) complex components Celsr1, Frizzled 6 and Vangl2, as shown in fly experiments ( Fig. 1Aii-iv) (Bökel et al, 2006;Coumailleau et al, 2009;Devenport et al, 2011;Cota and Davidson, 2015;Heck and Devenport, 2017). Interestingly, some CIE events also occur during mitosis, such as the clathrinindependent uptake of epidermal growth factor receptor (EGFR) (Liu et al, 2011) (Fig.…”

“…The usefulness of such residual CME has been questioned, but there are now several studies that provide direct evidence of uptake of endogenous cargos into dividing cells both in vitro and in vivo ( Fig. 1Aii-iv) (Bökel et al, 2006;Coumailleau et al, 2009;Devenport et al, 2011;Cota and Davidson, 2015;Heck and Devenport, 2017;Shrestha et al, 2015).…”

“…1D). Indeed, blocking their uptake during mitosis in vivo induced a defective partitioning between daughter cells, thereby severely compromising tissue polarity (Bökel et al, 2006;Heck and Devenport, 2017). By contrast, the biased partitioning of Notch and its ligand Delta as well as of FGFR during mitosis of fly and Ciona intestinalis stem cells mediates the asymmetrical fate of the daughter cells during organ development and polarization: the cell keeping the receptors has a different fate than the other cells (Cota and Davidson, 2015;Coumailleau et al, 2009;Derivery et al, 2015).…”

The crosstalk between microtubules, actin and membranes shapes cell division

“…The current view is that CME is not completely shut down during mitosis [123] and that the residual CME is critical to the internalization of specific cargoes in endosomes that are partitioned equally or asymmetrically between the two daughter cells. This is the case of the morphogen decapentaplegic (Dpp) in Drosophila or the planar cell polarity protein (PCP) complex in mouse that are vital to preserve tissue polarity and need to be inherited equally by daughter cells [124,125]. By contrast, the Notch receptor is internalized in SARA (smad anchor for receptor activation) endosomes that are partitioned asymmetrically and determine the different fates of the two daughter cells [126,127].…”

Gap junction internalization and processing in vivo: a 3D immuno-electron microscopy study

“…Gap junction internalization is therefore a type of endocytosis, in which the plasma membrane of the neighboring cell remains attached to the endocytosed plasma membrane (Heck and Devenport, 2017). Gap junction internalization can also be considered to be a form of trogocytosis (Joly and Hudriser, 2003) in which a portion of the plasma membrane and cytosol of the neighboring cell is transferred to the engulfing cell (See Fig.…”