Myelin is a distinctive feature of the vertebrate central nervous system (CNS). During CNS development, oligodendrocytes (OLs) wrap their membrane around axons to create an insulating, lipid-rich structure called the myelin sheath. While defects in axonal myelination are associated with multiple neurological disorders, including autism spectrum disorders, schizophrenia, and multiple sclerosis, we are only starting to uncover the mechanisms that regulate myelin development, maintenance, and remyelination. Cortical myelination is highly heterogeneous and follows a gradient distribution, with deep-layer projection neurons (PNs) being uniformly extensively myelinated, while upper-layer PNs have more diverse patterns and are more sparsely myelinated. OLs are a heterogenous population of cells with remarkable target specificity in vivo. However, the mechanisms underlying oligodendrocyte target selection are still unknown. Here, we applied single-cell molecular profiling of OLs across different cortical layers and across a postnatal time course to understand layer-specific differences in PN myelination. We found that while all cortical layers have a similar compendium of OL states, mature OLs are preferentially located in deep layers. To investigate if PN subtypes can guide oligodendrocyte maturation and myelination, we generated a predicted ligand-receptor interaction map between PNs subtypes and oligodendrocyte states across cortical layers and time. In vivo testing of candidate modulators of layer-specific myelination identified Fgf18 and Ncam1 as novel myelin-promoting molecules. Our results indicate that neuron-class-associated molecular signals can guide differential myelination across cortical layers.

To further understand the development and diversity of cortical myelination, our ongoing research aims at identifying the molecular signals that guide neuron-specific myelination patterns. This knowledge is fundamental to understanding the development and regeneration of myelin in the mammalian CNS.

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• https://scholar.google.com/citations?user=ebn4DNgAAAAJ&hl=en