Inhibition of N-cadherin and beta-catenin function reduces axon-induced Schwann cell proliferation

N-cadherin and beta-catenin have been postulated to have a dual role in cell adhesion and on cell cycle in different physiological and developmental stages and in various disease mechanisms. Little is known about the function of N-cadherin or beta-catenin in cell proliferation, cell death and cell adhesion in Schwann cells (SCs). We inhibited N-cadherin function using low Ca++ conditions and blocking antibodies and reduced beta-catenin expression using small interfering RNA (siRNA) in cultured adult rat-derived SCs and in dorsal root ganglion (DRG) cocultures. N-cadherin function blocking as well as beta-catenin knockdown decreased proliferation of cultured SCs. SiRNA-mediated knockdown of beta-catenin also increased apoptosis under basic culture conditions. Inhibition of beta-catenin interfered with the proliferative response of SCs to the mitogen beta1-heregulin, a main mediator of axon-dependent SC proliferation. In heregulin treated wild-type SC cultures upregulation and nuclear translocalization of beta-catenin was found. Axon-contact-dependent SC proliferation in SC-DRG cocultures was inhibited in beta-catenin knockdown SCs and in cultures in which N-cadherin function was blocked. These data suggest a previously unrecognized role of beta-catenin and N-cadherin in the regulation of heregulin- or axon-induced SC proliferation, potentially leading to new treatment options in peripheral demyelinating neuropathies and SC tumors.