Transcriptional dynamics of the oligodendrocyte lineage and its regulation by the brain erythropoietin system
Oligodendrocytes differentiate from oligodendrocyte precursor cells (OPC) in postnatal development but limited oligodendrogenesis is maintained throughout live. Oligodendrocyte lineage (OL) dynamics has been suggested to contribute to adult neuroplasticity, notably by adaptive myelination in response to sustained neuronal activity. However, mechanisms by which neuronal activity pushes oligodendrogenesis and/or myelination are unclear. Here, we explored novel aspects of OL dynamics, namely effects of recombinant human erythropoietin (rhEPO) and its receptor (EPOR) on OL in murine hippocampus. Using multiple stage-specific markers combined with single-nuclei-RNA-seq data, we found that rhEPO stimulates all OL cells and prompts oligodendroglial differentiation and maturation. Differential gene expression analysis reveals several EPO-regulated transcripts, including downregulation of GABA-A signaling, known to be associated with migration and OL progression. Importantly, analogous OL responses were seen when endogenous EPO expression in brain was stimulated by inspiratory (12%O2) or ′functional hypoxia′ through motor-cognitive challenge. Interestingly, mice lacking EPOR in mature oligodendrocytes show subtle defects of adult myelin in hippocampal fimbria, with a right shift in size distribution of myelinated axons. These mutants display mild working memory deficits, likely reflecting network dysfunction. Our data support a working model in which brain EPO, induced by functional hypoxia through continual neuronal activity, drives adaptive myelination.
Ye, L., Daguano Gastaldi, V., Curto, Y., Wildenburg, AF., Yu, X.*, Hindermann, M., Ronnenberg, A., Wang, Q., Butt, U. J., Kawaguchi, R., Geschwind, D., Möbius, W., Boretius, S., Nave, KA., Ehrenreich, H. (2024) Transcriptional dynamics of the oligodendrocyte lineage and its regulation by the brain erythropoietin system.
- shared first authorship