In the mouse embryonic forebrain, developmentally distinct oligodendrocyte progenitor cell populations and their progeny, oligodendrocytes, emerge from three distinct regions in a spatiotemporal gradient from ventral to dorsal. However, the functional importance of this oligodendrocyte developmental heterogeneity is unknown. Using a genetic strategy to ablate dorsally derived oligodendrocyte lineage cells (OLCs), we show here that the areas in which dorsally derived OLCs normally reside in the adult central nervous system 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 fully assume the role of the original dorsally derived cells results 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.We thank Dr Daniel Morrison, Matthew Gratian and Mark Bowen for technical support. Funding: This work was supported by the UK Multiple Sclerosis Society (RJMF/CZ), and The Adelson Medical Research Foundation (RJMF/DHR/K-AN/MR/DEB); the Swedish Research Council (grant 2015-03558 and 2019-01360), the European Union (Horizon 2020 Research and Innovation Programme/European Research Council Consolidator Grant EPIScOPE, grant agreement number 681893), the Swedish Brain Foundation (FO2017-0075), Knut and Alice Wallenberg Foundation (grant 2019-0107 and 2019-0089), The Swedish Society for Medical Research (SSMF, grant JUB2019), the G.ran Gustafsson Foundation for Research in Natural Sciences and Medicine, Strategic Research Programme in Neuroscience (StratNeuro), Ming Wai Lau Centre for Reparative Medicine and Karolinska Institutet (GC-B); the Medical Research Council (G0800575) (NK and WDR); a Project Grant from the National Centre for the Replacement, Refinement, & Reduction of Animals in Research (NC/N001451/1) (CJH,LLC, TJB, LMS); the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C2173) (EK, TJB, LMS); the NIH (AG072305) (DB); and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council
Cambridge Stem Cell Institute (203151/Z/16/Z). SF was supported by a PhD studentship from the
Wellcome Trust. TB is supported by a Junior Fellowship from the Loulou Foundation
