Merlin/ERM proteins establish cortical asymmetry and centrosome position

Abstract

The ability to generate asymmetry at the cell cortex underlies cell polarization and asymmetric cell division. Here we demonstrate a novel role for the tumor suppressor Merlin and closely related ERM proteins (Ezrin, Radixin, and Moesin) in generating cortical asymmetry in the absence of external cues. Our data reveal that Merlin functions to restrict the cortical distribution of the actin regulator Ezrin, which in turn positions the interphase centrosome in single epithelial cells and three-dimensional organotypic cultures. In the absence of Merlin, ectopic cortical Ezrin yields mispositioned centrosomes, misoriented spindles, and aberrant epithelial architecture. Furthermore, in tumor cells with centrosome amplification, the failure to restrict cortical Ezrin abolishes centrosome clustering, yielding multipolar mitoses. These data uncover fundamental roles for Merlin/ERM proteins in spatiotemporally organizing the cell cortex and suggest that Merlin's role in restricting cortical Ezrin may contribute to tumorigenesis by disrupting cell polarity, spindle orientation, and, potentially, genome stability.

Cerebrospinal fluid-derived Semaphorin3B orients neuroepithelial cell divisions in the apicobasal axis

“…Mitotic spindle orientation largely relies on astral microtubules and cortical actin cytoskeleton 15,16 . We hypothesized that extracellular signals known to regulate actin and microtubule dynamics, such as axon guidance cues, could be good candidates to influence cell division orientation.…”

ERM proteins at a glance

“…Cortical ezrin also undergoes a dynamic cell cycle-dependent redistribution in mammalian colonic epithelial (Caco2) cells; studies of this phenomenon uncovered a direct role for ezrin in orienting the centrosome and mitotic spindle (Hebert et al, 2012). When embedded in Matrigel, individual Caco2 cells undergo a well-studied program of polarized cyst formation (Jaffe et al, 2008).…”

“…When embedded in Matrigel, individual Caco2 cells undergo a well-studied program of polarized cyst formation (Jaffe et al, 2008). Recent studies have revealed that in single embedded Caco2 cells, ezrin is progressively restricted from a uniform cortical distribution into a discrete actin-rich cap-like structure in the absence of external spatial cues (Hebert et al, 2012). The ezrin 'cap' forms just prior to S phase and instructively positions the interphase centrosome and one pole of the ensuing mitotic spindle, likely providing a stiff platform for astral microtubule attachment.…”

“…The ezrin 'cap' forms just prior to S phase and instructively positions the interphase centrosome and one pole of the ensuing mitotic spindle, likely providing a stiff platform for astral microtubule attachment. At the metaphase-to-anaphase transition, ezrin vanishes from the polar cortex and reappears at the cleavage furrow, which becomes the nascent apical lumen around which cells divide to form a polarized cyst (Hebert et al, 2012).…”

“…Alternatively, notochord tubulogenesis in the ascidian Ciona intestinalis involves the formation of lumens along each of many lateral junctions between notochord cells, followed by rotation and fusion of the lumens to create a continuous tube; lumens do not form in the absence of Ci-ERM (Dong et al, 2011). In another example, the first division of single Caco2 cells in 3D culture features the redistribution of ezrin from the polar 'cap' to the cleavage furrow, which is converted into a cadherin-based junction and then into an apical lumen; cells subsequently divide symmetrically around the new central lumen to form a multicellular cyst (Hebert et al, 2012;Jaffe et al, 2008). Ezrin is required for lumen formation in this setting and ectopic cortical ezrin yields ectopic lumens.…”