Activin receptors regulate the oligodendrocyte lineage in health and disease
| Autor: | Julie-Clare Becher, Gloria H. Su, Graeme Ireland, Matthew Swire, Colin Smith, Anna Williams, Frances L. Evans, Marie E. Bechler, Alessandra Dillenburg, Daniel Soong, Tracy J. Yuen, Claire L. Davies, Veronique E. Miron, Rebecca K. Holloway |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Multiple Sclerosis Activin Receptors Biology Pathology and Forensic Medicine Rats Sprague-Dawley Tissue Culture Techniques Perinatal brain injury 03 medical and health sciences Cellular and Molecular Neuroscience Myelin 0302 clinical medicine Downregulation and upregulation medicine Journal Article Animals Humans Cell Lineage Remyelination Cells Cultured Mice Knockout Original Paper Tissue Scaffolds Oligodendrocyte differentiation Brain Cell Differentiation Activin receptor Oligodendrocyte 3. Good health Cell biology Mice Inbred C57BL Oligodendroglia 030104 developmental biology medicine.anatomical_structure Brain Injuries Female Neurology (clinical) 030217 neurology & neurosurgery ACVR2B ACVR2A |
| Zdroj: | Dillenburg, A, Ireland, G, Holloway, R K, Davies, C L, Evans, F L, Swire, M, Bechler, M E, Soong, D, Yuen, T J, Su, G H, Becher, J-C, Smith, C, Williams, A & Miron, V E 2018, ' Activin receptors regulate the oligodendrocyte lineage in health and disease ', Acta Neuropathologica, vol. 135, no. 6, pp. 887–906 . https://doi.org/10.1007/s00401-018-1813-3 Acta Neuropathologica |
| DOI: | 10.1007/s00401-018-1813-3 |
| Popis: | The most prevalent neurological disorders of myelin include perinatal brain injury leading to cerebral palsy in infants and multiple sclerosis in adults. Although these disorders have distinct etiologies, they share a common neuropathological feature of failed progenitor differentiation into myelin-producing oligodendrocytes and lack of myelin, for which there is an unmet clinical need. Here, we reveal that a molecular pathology common to both disorders is dysregulation of activin receptors and that activin receptor signaling is required for the majority of myelin generation in development and following injury. Using a constitutive conditional knockout of all activin receptor signaling in oligodendrocyte lineage cells, we discovered this signaling to be required for myelination via regulation of oligodendrocyte differentiation and myelin compaction. These processes were found to be dependent on the activin receptor subtype Acvr2a, which is expressed during oligodendrocyte differentiation and axonal ensheathment in development and following myelin injury. During efficient myelin regeneration, Acvr2a upregulation was seen to coincide with downregulation of Acvr2b, a receptor subtype with relatively higher ligand affinity; Acvr2b was shown to be dispensable for activin receptor-driven oligodendrocyte differentiation and its overexpression was sufficient to impair the abovementioned ligand-driven responses. In actively myelinating or remyelinating areas of human perinatal brain injury and multiple sclerosis tissue, respectively, oligodendrocyte lineage cells expressing Acvr2a outnumbered those expressing Acvr2b, whereas in non-repairing lesions Acvr2b+ cells were increased. Thus, we propose that following human white matter injury, this increase in Acvr2b expression would sequester ligand and consequently impair Acvr2a-driven oligodendrocyte differentiation and myelin formation. Our results demonstrate dysregulated activin receptor signaling in common myelin disorders and reveal Acvr2a as a novel therapeutic target for myelin generation following injury across the lifespan. Electronic supplementary material The online version of this article (10.1007/s00401-018-1813-3) contains supplementary material, which is available to authorized users. |
| Databáze: | OpenAIRE |
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