Neuronal-class specific molecular cues drive differential myelination in the cortex

Myelination represents a unique milestone in vertebrate brain evolution that has enabled the expansion of the brain and emergence of complex neurological functions. Oligodendrocytes are a heterogeneous population of cells that differentially myelinate specific neuronal subtypes, resulting in characteristic amounts and patterns of axonal myelination for each neuronal class across the cortical layers. The molecular mechanisms by which neurons communicate with oligodendrocytes to direct subtype-specific myelination remain to be understood. Here, we generated a single-cell molecular map of cortical oligodendrocyte-lineage cells across the different cortical layers, over a time course spanning the process of myelination. We find that mature, myelinating oligodendrocytes are transcriptionally heterogenous, and that more mature subtypes are enriched in the deep layers. We applied differential gene expression analysis of myelinating oligodendrocytes and weakly-myelinated upper-layer projection neurons vs heavily- myelinated deep-layer projection neurons to identify candidate genes that mediate neuronal subtype-specific myelination. We show that deep-layer-specific candidate genes drive an increase in myelination when misexpressed in the upper cortical layers, which is synergistically increased when these candidate factors are co-expressed. Our results demonstrate that gene- expression signatures are essential for neuronal cell-type specific myelin targeting. Identifying these molecular players may offer new therapeutic opportunities for treating demyelinating disorders.