Dataset Information

Primary cilia control oligodendrocyte precursor cell proliferation in white matter injury via Hedgehog-independent CREB signaling.

ABSTRACT: Remyelination after white matter injury (WMI) often fails in diseases such as multiple sclerosis because of improper recruitment and repopulation of oligodendrocyte precursor cells (OPCs) in lesions. How OPCs elicit specific intracellular programs in response to a chemically and mechanically diverse environment to properly regenerate myelin remains unclear. OPCs construct primary cilia, specialized signaling compartments that transduce Hedgehog (Hh) and G-protein-coupled receptor (GPCR) signals. We investigated the role of primary cilia in the OPC response to WMI. Removing cilia from OPCs genetically via deletion of Ift88 results in OPCs failing to repopulate WMI lesions because of reduced proliferation. Interestingly, loss of cilia does not affect Hh signaling in OPCs or their responsiveness to Hh signals but instead leads to dysfunctional cyclic AMP (cAMP)-dependent cAMP response element-binding protein (CREB)-mediated transcription. Because inhibition of CREB activity in OPCs reduces proliferation, we propose that a GPCR/cAMP/CREB signaling axis initiated at OPC cilia orchestrates OPC proliferation during development and in response to WMI.

SUBMITTER: Hoi KK

PROVIDER: S-EPMC10715572 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Primary cilia control oligodendrocyte precursor cell proliferation in white matter injury via Hedgehog-independent CREB signaling.

Hoi Kimberly K KK Xia Wenlong W Wei Ming Ming MM Ulloa Navas Maria Jose MJ Garcia Verdugo Jose-Manuel JM Nachury Maxence V MV Reiter Jeremy F JF Fancy Stephen P J SPJ

Cell reports 20231017 10

Remyelination after white matter injury (WMI) often fails in diseases such as multiple sclerosis because of improper recruitment and repopulation of oligodendrocyte precursor cells (OPCs) in lesions. How OPCs elicit specific intracellular programs in response to a chemically and mechanically diverse environment to properly regenerate myelin remains unclear. OPCs construct primary cilia, specialized signaling compartments that transduce Hedgehog (Hh) and G-protein-coupled receptor (GPCR) signals. ...[more]

PMID: 37858465

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Project description:BackgroundChronic cerebral hypoperfusion-induced demyelination causes progressive white matter injury, although the pathogenic pathways are unknown.MethodsThe Single Cell Portal and PanglaoDB databases were used to analyze single-cell RNA sequencing experiments to determine the pattern of EAAT3 expression in CNS cells. Immunofluorescence (IF) was used to detect EAAT3 expression in oligodendrocytes and oligodendrocyte progenitor cells (OPCs). EAAT3 levels in mouse brains were measured using a western blot at various phases of development, as well as in traumatic brain injury (TBI) and intracerebral hemorrhage (ICH) mouse models. The mouse bilateral carotid artery stenosis (BCAS) model was used to create white matter injury. IF, Luxol Fast Blue staining, and electron microscopy were used to investigate the effect of remyelination. 5-Ethynyl-2-Deoxy Uridine staining, transwell chamber assays, and IF were used to examine the effects of OPCs' proliferation, migration, and differentiation in vivo and in vitro. The novel object recognition test, the Y-maze test, the rotarod test, and the grid walking test were used to examine the impact of behavioral modifications.ResultsA considerable amount of EAAT3 was expressed in OPCs and mature oligodendrocytes, according to single-cell RNA sequencing data. During multiple critical phases of mouse brain development, there were no substantial changes in EAAT3 levels in the hippocampus, cerebral cortex, or white matter. Furthermore, neither the TBI nor ICH models significantly affected the levels of EAAT3 in the aforementioned brain areas. The chronic white matter injury caused by BCAS, on the other hand, resulted in a strikingly high level of EAAT3 expression in the oligodendroglia and white matter. Correspondingly, blocking EAAT3 assisted in the recovery of cognitive and motor impairment as well as the restoration of cerebral blood flow following BCAS. Furthermore, EAAT3 suppression was connected to improved OPCs' survival and proliferation in vivo as well as faster OPCs' proliferation, migration, and differentiation in vitro. Furthermore, this study revealed that the mTOR pathway is implicated in EAAT3-mediated remyelination.ConclusionsOur findings provide the first evidence that abnormally high levels of oligodendroglial EAAT3 in chronic cerebral hypoperfusion impair OPCs' pro-remyelination actions, hence impeding white matter repair and functional recovery. EAAT3 inhibitors could be useful in the treatment of ischemia demyelination.

Dataset Information

Primary cilia control oligodendrocyte precursor cell proliferation in white matter injury via Hedgehog-independent CREB signaling.

Publications

Primary cilia control oligodendrocyte precursor cell proliferation in white matter injury via Hedgehog-independent CREB signaling.

Similar Datasets

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