Peripheral myelin protein 22 (PMP22) is associated with a subset of hereditary peripheral neuropathies. Although predominantly recognized as a transmembrane constituent of peripheral nerve myelin, PMP22 is localized to epithelial and endothelial cell-cell junctions, where its function remains unknown. In this report, we investigated the role of PMP22 in epithelial biology. Expression of human PMP22 (hPMP22) slows cell growth and induces a flattened morphology in Madin-Darby canine kidney (MDCK) cells. The transepithelial electrical resistance (TER) and paracellular flux of MDCK monolayers are elevated by hPMP22 expression. After calcium switch, peptides corresponding to the second, but not the first, extracellular loop of PMP22 perturb the recovery of TER and paracellular flux. Finally, subsequent to wounding, epithelial monolayers expressing hPMP22 fail to migrate normally. These results indicate that PMP22 is capable of modulating several aspects of epithelial cell biology, including junctional permeability and wound closure.
INTRODUCTIONThe tetraspan glycoprotein peripheral myelin protein 22 (PMP22), also known as growth arrest specific 3 (gas3) gene, has proposed roles in peripheral nerve myelin formation, cell-cell interactions, and cell proliferation (Suter and Snipes, 1995). Although the highest expression levels are found in myelin-forming Schwann cells, PMP22 mRNA can be detected in a multitude of developing and mature nonneural tissues, including epithelia of the intestine (Baechner et al., 1995;Taylor et al., 1995;Wulf and Suter, 1999) and the choroid plexus (Roux et al., 2004). The specific role of PMP22 in Schwann cells remains undefined, although it is known that altered expression is associated with heritable demyelinating peripheral neuropathies (Naef and Suter, 1998). Similarly, the function of the protein at nonneural locations remains undetermined.In vitro studies have identified a role for PMP22 in the regulation of cell proliferation and morphology. In Schwann cells, elevated expression delays the transition from G0/G1 to the S phase of the cell cycle (Zoidl et al., 1995), and can lead to apoptosis in some instances (Fabbretti et al., 1995;Zoidl et al., 1997). Conversely, reduced PMP22 mRNA levels are associated with enhanced DNA synthesis and entry into the S ϩ G2/M phases (Zoidl et al., 1995). In NIH 3T3 fibroblasts, PMP22 overexpression regulates cell spreading, an effect that is dependent on the Rho-GTPase pathway (Brancolini et al., 1999). Recent studies have detected exogenous PMP22 in ADP-ribosylation factor 6 (Arf-6)-positive plasma membrane-endosomal recycling vacuoles before apoptosis or changes in cell shape (Chies et al., 2003). This pathway is known to be involved in modulating the actin cytoskeleton, cell polarity, adhesion, and migration (Donaldson, 2003). Together, these findings support the notion that PMP22 has a significant role in basic cellular processes, extending beyond an involvement in Schwann cell myelination.We previously described PMP22 as a constituent of apical ...