Asymmetric Protein Localization in Planar Cell Polarity

Abstract

The polarization of epithelial cells along an axis orthogonal to their apical–basal axis is increasingly recognized for roles in a variety of developmental events and physiological functions. While now studied in many model organisms, mechanistic understanding is rooted in intensive investigations of planar cell polarity (PCP) in Drosophila. Consensus has emerged that two molecular modules, referred to here as the global and core modules, operate upstream of effector proteins to produce morphological PCP. Proteins of the core module develop subcellular asymmetry, accumulating in two groups on opposite sides of cells, consistent with proposed functions in producing cell polarity and in communicating that polarity between neighboring cells. Less clear are the molecular and cell biological mechanisms underlying core module function in the generation and communication of subcellular asymmetry and the relationship between the global and the core modules. In this review, we discuss these two unresolved questions, highlighting important studies and potentially enlightening avenues for further investigation. It is likely that results from Drosophila will continue to inform our views of the growing list of examples of PCP in vertebrate systems.

Introduction

It is well appreciated that most cells assemble highly polarized structures that are essential for their specialized functions. In epithelial cells, the most obvious polarized feature is the universal apical–basal polarity that distinguishes the cell surface facing the external environment or lumen from that adjacent to the basal lamina. Extensive studies have revealed essential roles of apical–basal polarity in carrying out epithelial function and maintaining tissue homeostasis. At the same time, it has also been appreciated that epithelial cells can be polarized along the tissue surface, on an axis perpendicular to the apical–basal axis. This polarity, called planar cell polarity (PCP), is apparent in many epithelia in multicellular organisms. Understanding of the physiological significance of PCP, though often less apparent, has been steadily growing with the recent intensification of molecular genetic studies in various model organisms (Goodrich & Strutt, 2011). These efforts have shown that regulation of cellular function by PCP is important for processes including tissue morphogenesis (Keller, 2002), directional cell migration (Wada & Okamoto, 2009), and directional mechanosensing (Kelly & Chen, 2007) and will be discussed in other reviews in this volume.

While control of PCP is largely distinct from that of apical–basal polarity, the core families of PCP proteins localize and appear to act apically at the adherens junctions (Goodrich & Strutt, 2011). As first discovered during acquisition of planar polarity in the Drosophila wing epithelium (Axelrod, 2001, Strutt, 2001), those proteins become asymmetrically localized in a highly stereotypical manner, such that a distal subset localizes at the distal cell cortex and interacts with a proximal subset in the neighboring cell, and vice versa, resulting in the polarized localization of both proximal and distal components within each cell (Vladar, Antic, & Axelrod, 2009). In this review, we focus on our current understanding of the mechanisms that give rise to this asymmetric protein localization. We suggest that asymmetric protein localization is a characteristic and essential feature of planar-polarized epithelia, based on a growing list of examples from both invertebrate and vertebrate systems. The majority of this review discusses possible cell-autonomous and non-cell-autonomous mechanisms through which asymmetric protein localization arises. Our current understanding is based largely on experimental studies with Drosophila wing epithelium, in combination with mathematical simulations that examine the properties of proposed models. While studies with vertebrate models have to date yielded less mechanistic insight, numerous observations suggest substantial mechanistic conservation (Mitchell et al., 2009, Sienknecht et al., 2011).

We begin with a brief discussion of the three modules of planar polarity genes and propose a hierarchical structure, a model first developed almost a decade ago (Tree, Ma, & Axelrod, 2002). Despite the elapsed time, the mechanisms underlying this organization have not been revealed. We believe that the model has proved to be a valid general framework for understanding PCP, despite some recent challenges, and that clarifying mechanisms will soon emerge. Given its controversial nature, the model deserves a quick revisit here.