Molecular cues from distinct neuron classes drive differential myelination in the neocortex

Oligodendrocytes deposit different amounts of myelin in each neocortical layer, but the regulatory process remains unclear. We present a single-cell map of oligodendrocyte lineage cells purified from different layers of the neocortex across developmental stages. We find that each layer contains a similar compendium of oligodendrocyte classes and differs primarily in the proportions of maturation states, suggesting that oligodendrocyte heterogeneity cannot explain layer-specific myelination. We show that signals from different classes of pyramidal neurons can control oligodendrocyte maturation and the differential distribution of myelin across cortical layers. We generated a ligand-receptor interactome to predict interactions between projection neuron types and oligodendrocyte states, across cortical layers and time, and validated candidates in vivo. We find that neuronal expression of Fgf18, Ncam1, and Rspo3 promotes cortical myelination. This work provides a comprehensive molecular description of oligodendrocyte development in the mouse cortex, pointing to mechanisms whereby neuron-class-linked signals modulate myelin distribution in the neocortex.