Activin receptors regulate the oligodendrocyte lineage in health and disease

Abstract

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 materialThe online version of this article (10.1007/s00401-018-1813-3) contains supplementary material, which is available to authorized users.

Heterogeneity of microglia and their differential roles in white matter pathology

“…87 Moreover, multiple factors including activin A, galectin-3, and insulin-like growth factor 1 (IGF1) were produced by microglia which supported oligodendrocyte differentiation in vivo. [88][89][90] Interestingly, TNFα and IL-1β, mentioned earlier as oligodendrocyte-damaging factors secreted by microglia, were found to play beneficial roles in remyelination as well along with other pro-inflammatory factors such as CXCL13 and endothelin-2. [91][92][93] These contrasting effects were driven by time- mRNAs were increased and facilitated remyelination in mice MS models.…”

“…Transforming growth factor α (TGFα) was also found to be secreted by microglia after ischemic damage and showed protective roles on OPCs and oligodendrocytes in vitro and contributed to white matter integrity in vivo . Moreover, multiple factors including activin A, galectin‐3, and insulin‐like growth factor 1 (IGF1) were produced by microglia which supported oligodendrocyte differentiation in vivo . Interestingly, TNFα and IL‐1β, mentioned earlier as oligodendrocyte‐damaging factors secreted by microglia, were found to play beneficial roles in remyelination as well along with other pro‐inflammatory factors such as CXCL13 and endothelin‐2 .…”

Astrocytes and Microglia as Major Players of Myelin Production in Normal and Pathological Conditions

“…This growth factor regulates oligodendrocyte differentiation and myelin compaction via the activin receptor subtype Acvr2a up-regulated during efficient myelin regeneration, in contrast to the other receptor subtype Acvr2b, which has to be down-regulated for allowing oligodendrocyte differentiation. In actively remyelinating areas of MS tissue, oligodendrocyte lineage cells expressing Acvr2a consistently outnumber cells expressing Acvr2b suggesting that an increase in Acvr2b expression may impair oligodendrocyte differentiation and myelin formation induced by Acvr2a (Dillenburg et al, 2018).…”

Inactivation of LCN2/EGR1 Promotes Oligodendrocyte Progenitor Cell Differentiation and Remyelination after White Matter Injury

“…3a, b, e). The persistent enlargement of inner tongues may thus result either from increased membrane growth rate or impaired actin disassembly and myelin membrane compaction (Dillenburg et al, 2018). To address these hypotheses, we first measured the thickness of compacted layers because an increased membrane growth rate would result in a thicker myelin sheath.…”

“…Genomic DNA was extracted from tail tissue using the Wizard SV genomic purification system (Promega Biotech, Beijing, China) according to the manufacturer's instructions. EGR1 floxed mice were genotyped using PCR strategies as previously described (Dillenburg et al, 2018). Briefly, EGR1…”