A gain-of-function Retsat variant from high-altitude adaptation promotes myelination via a neuronal dihydroretinoic...

Evolutionary adaptations provide a powerful lens for discovering fundamental regulators. By studying a Retsat variant (Q247R) found in high-altitude-adapted species, we reveal a central pathway governing CNS myelination and repair. Mice harboring this variant show reduced neonatal hypoxia-induced hypomyelination and exhibit enhanced remyelination in adulthood. The variant exhibits heightened enzymatic activity, driving increased neuronal production of all-trans-13,14-dihydroretinol (ATDR). By ruling out an intrinsic role in oligodendrocytes, we define this pathway as non-cell autonomous. ATDR is converted in neurons to all-trans-dihydroretinoic acid, which acts as a neuron-to-glia paracrine signal to activate the RXR-γ pathway in oligodendrocyte progenitor cells, thereby stimulating their differentiation and myelination. Administration of ATDR, a prodrug, potently promotes remyelination in multiple myelin injury models. Our work identifies Retsat and dihydroretinoids as pivotal regulators of white matter integrity and as a promising therapeutical avenue inspired by evolutionary genetics for white matter diseases.