SECISBP2L-mediated selenoprotein synthesis is essential for autonomous regulation of oligodendrocyte differentiation

Abstract

Thyroid hormone controls the timely differentiation of oligodendrocytes (OLs), and its deficiency can delay myelin development and cause mental retardation. Previous studies showed that the active thyroid hormone T3 is converted from its prohormone T4 by the selenoprotein DIO2, whose mRNA is primarily expressed in astrocytes in the central nervous system. In the present study, we discovered that SECISBP2L is highly expressed in differentiating OLs and is required for DIO2 translation. Conditional knockout of Secisbp2l in OL lineage resulted in a decreased level of DIO2 and T3, accompanied by impaired OL differentiation, hypomyelination and motor deficits in both sexes of mice. Moreover, the defective differentiation of OLs in Secisbp2l mutants can be alleviated by T3 or its analog, but not the prohormone T4. The present study has provided strong evidence for the autonomous regulation of OL differentiation by its intrinsic T3 production mediated by the novel SECISBP2LDIO2-T3 pathway during myelin development.