Developmental origin of oligodendrocytes determines their function in the adult brain

The functional importance of oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally-derived oligodendrocyte lineage cells (OLCs), we found that the areas in which dorsally-derived OLCs normally reside in the adult CNS become populated and myelinated by OLCs of ventral origin. These ectopic oligodendrocytes (eOLs) have a distinctive gene expression profile, as well as subtle myelination abnormalities. The failure of eOLs to assume the role of the original dorsally-derived cells result in locomotor and cognitive deficits in the adult animal. This study reveals the importance of developmental heterogeneity within the oligodendrocyte lineage, and its importance for homeostatic brain function. Sox10-loxP-eGFP-polyA-STOP-loxP-tdTomato (hereafter abbreviated as ‘Sox10-GFP-tdTom’ or ‘Tom’) reporter mice​​ express enhanced GFP in all oligodendrocyte lineage cells (OLCs) in the absence of Cre activity. To differentially label ventrally- and dorsally-derived OLCs in the forebrain, Sox10-GFP-tdTom mice were crossed to Emx1-Cre mice (hereafter abbreviated as ‘Emx’)​​. To study the functional importance of dorsally-derived OLCs in the adult brain, dorsally-derived, Emx1-positive OLCs were ablated by crossing the Emx1-Cre line to the Sox10-loxP-GFP-poly(A)-STOP-loxP-DTA (hereafter abbreviated as ‘Sox10-DTA’ or ‘DTA’) mouse line​. To determine the ablation efficiency, all three mouse lines were crossed (hereafter abbreviated as ‘Emx/Tom/DTA’), allowing the visualization of the remaining dorsally-derived OLCs after ablation. Mouse strains used for RNA-sequencing: Control: Emx/Tom, Ablated: Emx/Tom/DTA