ABSTRACT
Understanding the mechanisms that control myelin formation is essential for the development of demyelinating diseases treatments. All-trans-retinoic acid (RA) plays an essential role during the development of the nervous system as a potent regulator of morphogenesis, cell growth, and differentiation. In this study, we show that RA is also a potent inhibitor of peripheral nervous system (PNS) myelination. RA acts through its binding to RA receptors (RAR) and retinoid X receptors (RXR), two members of the superfamily of nuclear receptors that act as ligand-dependent transcription factors. Schwann cells (SCs) express all retinoid receptors during the relevant stages of myelin formation. Through the activation of RXR, RA produces an upregulation of Krox20, a SC-specific regulatory transcription factor that plays a central role during myelination. Krox20 upregulation translates into Mbp and Mpz overexpression, therefore blocking myelin formation. This increase in myelin protein expression is accompanied by the induction of an adaptive ER stress response. At the same time, through a RAR-dependent mechanism, RA downregulates myelin-associated glycoprotein, which also contributes to the dysmyelinating effect of the retinoid.
