Jcb_200812034 779..786

Regulation of cell polarity and orientation is essential during symmetric and asymmetric cell division and cell differentiation, as well as in a large variety of cellular functions such as T cell interaction with their target cell, synaptic transmission, or cell migration (Krummel and Macara, 2006; Arimura and Kaibuchi, 2007; Etienne-Manneville, 2008). Directed as well as random cell migration is associated with polarization of the cellular machinery in order to define a leading protrusive front and a retracting rear. During cell migration as well as during cell differentiation or polarized cell function, the relative position of the centrosome and the nucleus is generally a good indicator of the orientation of the cell polarity axis (Schliwa et al., 1999; de Anda et al., 2005; Siegrist and Doe, 2006). Integrin engagement with the extracellular matrix plays a key role in controlling nucleus and centrosome positioning in migrating and immobile cells (Etienne-Manneville and Hall, 2001; Thery et al., 2005, 2006; Peng et al., 2008). In contrast, the role of cell–cell contacts in controlling orientation of the nucleus–centrosome axis remains unclear. Tight junctions are key to the baso-apical polarity of epithelial cells, and are likely to be involved in centrosome apical positioning (Musch, 2004; Shin et al., 2006). Herein, we investigated whether intercellular junctions can promote polarization of nonepithelial cells, such as astrocytes, that do not form tight junctions. We show that anisotropic cell–cell interactions provide extracellular cues that are sufficient to promote cell polarization and orientation toward the free cell edge. In the absence of any other polarizing cues, calcium-dependent classical cadherins, including N-cadherin as well as E-cadherin, control centrosome and nucleus positioning and cell polarization via the regulation of cell interactions with the extracellular matrix and of the actin and microtubule cytoskeletons.