Mitotic internalization of planar cell polarity proteins preserves tissue polarity

Abstract

Planar cell polarity (PCP) is the collective polarization of cells along the epithelial plane, a process best understood in the terminally differentiated Drosophila wing. Proliferative tissues such as mammalian skin also display PCP, but the mechanisms that preserve tissue polarity during proliferation are not understood. During mitosis, asymmetrically-distributed PCP components risk mislocalisation or unequal inheritance, which could have profound consequences on the long-range propagation of polarity. Here, we show that when mouse epidermal basal progenitors divide, PCP components are selectively internalized into endosomes, which are inherited equally by daughter cells. Following mitosis, PCP proteins are recycled to the cell surface where asymmetry is re-established by a process reliant upon neighbouring PCP. A cytoplasmic dileucine motif governs mitotic internalization of atypical cadherin Celsr1, which recruits Vang2 and Fzd6 to endosomes. Moreover, embryos transgenic for a Celsr1 that cannot mitotically internalize, exhibit perturbed hair follicle angling, a hallmark of defective PCP. This underscores the physiological relevance and importance of this novel mechanism for regulating polarity during cell division.

Cofilin and Vangl2 cooperate in the initiation of planar cell polarity in the mouse embryo

“…Consistent with those observations, we observe that loss of actin severing disrupts the association of Rab11 + vesicles with the plasma membrane and leads to accumulation of Rab11 + Celsr1 + vesicles in the apical domain of node cells, arguing that Rab11 + vesicles are crucial targets of cofilin-regulated trafficking in PCP. It has previously been shown that planar polarity is maintained through cell division by regulated internalization and retargeting of PCP proteins during mitosis, and more than 70% of the Celsr1 + vesicles are also Rab11 + in that context (Devenport et al, 2011). Our results suggest that the initial targeting of PCP proteins to the cell surface follows a similar pathway.…”

Clathrin-mediated endocytosis is inhibited during mitosis

“…In some specialized cases, there is good evidence for an override mechanism. For example, the atypical cadherin Celsr1, which is internalized to maintain an asymmetric distribution at the plasma membrane (45). This protein uses a dileucine sorting motif for internalization, and this phenomenon seems to be particular to this planar cell polarity component.…”

Planar cell polarity in moving cells: think globally, act locally

“…With few exceptions, the relationship between core PCP components in vertebrate epithelial cells is the same as in flies, with Fzd and Dvl localizing together, opposite Vangl and Prickle (hereafter Pk) (Fig. 1B-D) (Butler and Wallingford, 2015;Chu and Sokol, 2016;Ciruna et al, 2006;Davey et al, 2016;Deans et al, 2007;Devenport et al, 2011;Hashimoto et al, 2010;Vladar et al, 2012;Yin et al, 2008). Altering the expression of Vang or Fz homologs mosaically in the frog skin or in the sensory epithelium of the chick ear disrupts the polarity of adjacent wild-type cells, suggesting that the molecular interactions between core PCP components that amplify and maintain their asymmetric localization are conserved between fly and vertebrate epithelia (Mitchell et al, 2009;Sienknecht et al, 2011).…”

“…Insights into the role of asymmetrically localized PCP components during neuroepithelial morphogenesis have been provided by studies of zebrafish, in which it was shown that Vangl2 mutant cells in the neural keel are unable to re-intercalate into the neuroepithelium after undergoing mediolaterally oriented divisions (Ciruna et al, 2006). Indeed, dividing epithelial cells round up and temporarily lose their polarity, and PCP signaling is a general mechanism by which interphase cells can inform newly divided neighbors about tissue polarity (Devenport et al, 2011). PCP asymmetry might thus serve more to facilitate tissue integrity -analogous to the stacking system of Lego bricks -than to drive morphogenesis directly.…”