RXR Gamma Enables Oligodendrocyte Differentiation by Suppressing Sonic Hedgehog Signaling

Overcoming remyelination failure is one of the main targets in therapeutic strategies for multiple sclerosis. This process requires the differentiation of oligodendrocyte precursor cells (OPCs) to mature myelinating oligodendrocytes (OLs), a process known to be controlled by thyroid hormone, nuclear receptors, and sonic hedgehog (SHH). Retinoid X receptor gamma (RXRg) is one of the nuclear receptors acting as a positive regulator of remyelination, but little is known about its mechanisms of function. Using transcriptomic and pharmacological analysis of primary neural stem cell-derived OPCs, we show that RXRg is involved in the induction of the thyroid hormone-driven differentiation process and in refining it toward an oligodendrogenic cell fate. RXRg also emerged as an important negative modulator of SHH expression and signaling, as Shh and additional genes from this pathway were found to be strongly upregulated in Rxrg^-/- OPCs. An inhibition of SHH signaling by cyclopamine or GANT61 entirely normalized the differentiation deficit of Rxrg^-/- OPCs, but also myelination of newly generated Rxrg^-/- OLs. Such data indicate a key role of SHH hyperactivity in the oligodendrogenesis block associated with the absence of RXRg. Importantly, hyperactivation of the SHH pathway by purmorphamine or SAG inhibited the oligodendrogenesis and myelination potential of wild-type OPCs, indicating that SHH hyperactivity can also be a sufficient factor to block OPC differentiation. These results point to RXRg as an important regulator of SHH pathway signaling and underline the need of an optimal, fine-tuning of SHH signaling to assure successful oligodendrogenesis.