MOLECULAR MECHANISMS GOVERNING PROJECTION-NEURON-SPECIFIC MYELINATION IN THE CORTEX

Cerebral cortex development is essential for sensory and cognitive functions, with myelination playing a central role. Myelination varies greatly across and within different brain regions. In the cerebral cortex, deep-layer projection neurons (PNs) are uniformly and extensively myelinated, while upper-layer PNs exhibit diverse and sparse myelination patterns. Although defects in axonal myelination have been implicated in neurological disorders, the mechanisms that regulate myelin development, maintenance, and remyelination remain poorly understood.

Oligodendrocytes are a heterogenous population of cells with remarkable target specificity in vivo, yet the mechanisms underlying oligodendrocyte target selection are still largely unknown. In this study, we sought to uncover mechanisms regulating differential myelination across diverse PN subtypes in the cerebral cortex. We generated a transcriptomic atlas of oligodendrocytes across cortical layers and tracked their maturation over postnatal development. While all cortical layers have a similar compendium of oligodendrocytes states, mature oligodendrocytes were preferentially located in deep layers. To explore whether PN subtypes can guide oligodendrocyte maturation and myelination, we utilized CellPhoneDB to predict ligand-receptor interactions between PNs subtypes and oligodendrocytes states across cortical layers and developmental stages. In vivo validation of candidate modulators of layer-specific myelination identified Fgf18 and Ncam1 as novel myelin-promoting molecules in the cerebral cortex. Our results indicate that neuron-class-associated molecular signals can guide differential myelination across cortical layers.

Our ongoing work aims to identifying molecular signals that guide neuron-specific myelination patterns. Deciphering the mechanisms underlying selective myelination is fundamental to understand not only the principles driving myelin development but also its regeneration in disease.