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Oligodendrocyte precursor cells (OPCs) undergo an extensive and coordinated migration in the developing CNS, using the pre-formed scaffold of developed blood vessels as their physical substrate for migration. While OPC association with vasculature is critical for dispersal, equally important for permitting differentiation and proper myelination of target axons is their appropriate and timely detachment, but regulation of this process remains unclear. Here we demonstrate a correlation between the developmental formation of astrocytic endfeet on vessels and the termination of OPC perivascular migration. Ex vivo and in vivo live imaging shows that astrocyte endfeet physically displace OPCs from vasculature, and genetic abrogation of endfoot formation hinders both OPC detachment from vessels and subsequent differentiation. Astrocyte-derived semaphorins 3a and 6a act to repel OPCs from blood vessels at the cessation of their perivascular migration and, in so doing, permit subsequent OPC differentiation by insulating them from a maturation inhibitory endothelial niche.

Oligodendrocyte (OL) maturation arrest in human white matter injury contributes significantly to the failure of endogenous remyelination in multiple sclerosis (MS) and newborn brain injuries such as hypoxic ischemic encephalopathy (HIE) that cause cerebral palsy. In this study, we identify an oligodendroglial-intrinsic factor that controls OL maturation specifically in the setting of injury. We find a requirement for the ring finger protein Rnf43 not in normal development but in neonatal hypoxic injury and remyelination in the adult mammalian CNS. Rnf43, but not the related Znrf3, is potently activated by Wnt signaling in OL progenitor cells (OPCs) and marks activated OPCs in human MS and HIE. Rnf43 is required in an injury-specific context, and it promotes OPC differentiation through negative regulation of Wnt signal strength in OPCs at the level of Fzd1 receptor presentation on the cell surface. Inhibition of Fzd1 using UM206 promotes remyelination following ex vivo and in vivo demyelinating injury.

Disruption of the blood-brain barrier (BBB) is critical to initiation and perpetuation of disease in multiple sclerosis (MS). We report an interaction between oligodendroglia and vasculature in MS that distinguishes human white matter injury from normal rodent demyelinating injury. We find perivascular clustering of oligodendrocyte precursor cells (OPCs) in certain active MS lesions, representing an inability to properly detach from vessels following perivascular migration. Perivascular OPCs can themselves disrupt the BBB, interfering with astrocyte endfeet and endothelial tight junction integrity, resulting in altered vascular permeability and an associated CNS inflammation. Aberrant Wnt tone in OPCs mediates their dysfunctional vascular detachment and also leads to OPC secretion of Wif1, which interferes with Wnt ligand function on endothelial tight junction integrity. Evidence for this defective oligodendroglial-vascular interaction in MS suggests that aberrant OPC perivascular migration not only impairs their lesion recruitment but can also act as a disease perpetuator via disruption of the BBB.

Oligodendrocyte progenitor cells (OPC) undergo asymmetric cell division (ACD) to generate one OPC and one differentiating oligodendrocyte (OL) progeny. Loss of pro-mitotic proteoglycan and OPC marker NG2 in the OL progeny is the earliest immunophenotypic change of unknown mechanism that indicates differentiation commitment. Here, we report that expression of the mouse homolog of Drosophila tumor suppressor Lethal giant larvae 1 (Lgl1) is induced during OL differentiation. Lgl1 conditional knockout OPC progeny retain NG2 and show reduced OL differentiation, while undergoing more symmetric self-renewing divisions at the expense of asymmetric divisions. Moreover, Lgl1 and hemizygous Ink4a/Arf knockouts in OPC synergistically induce gliomagenesis. Time lapse and total internal reflection microscopy reveals a critical role for Lgl1 in NG2 endocytic routing and links aberrant NG2 recycling to failed differentiation. These data establish Lgl1 as a suppressor of gliomagenesis and positive regulator of asymmetric division and differentiation in the healthy and demyelinated murine brain.

Hypoxia can injure brain white matter tracts, comprised of axons and myelinating oligodendrocytes, leading to cerebral palsy in neonates and delayed post-hypoxic leukoencephalopathy (DPHL) in adults. In these conditions, white matter injury can be followed by myelin regeneration, but myelination often fails and is a significant contributor to fixed demyelinated lesions, with ensuing permanent neurological injury. Non-myelinating oligodendrocyte precursor cells are often found in lesions in plentiful numbers, but fail to mature, suggesting oligodendrocyte precursor cell differentiation arrest as a critical contributor to failed myelination in hypoxia. We report a case of an adult patient who developed the rare condition DPHL and made a nearly complete recovery in the setting of treatment with clemastine, a widely available antihistamine that in preclinical models promotes oligodendrocyte precursor cell differentiation. This suggested possible therapeutic benefit in the more clinically prevalent hypoxic injury of newborns, and we demonstrate in murine neonatal hypoxic injury that clemastine dramatically promotes oligodendrocyte precursor cell differentiation, myelination, and improves functional recovery. We show that its effect in hypoxia is oligodendroglial specific via an effect on the M1 muscarinic receptor on oligodendrocyte precursor cells. We propose clemastine as a potential therapy for hypoxic brain injuries associated with white matter injury and oligodendrocyte precursor cell maturation arrest.

Oligodendrocytes myelinate axons in the central nervous system and develop from oligodendrocyte precursor cells (OPCs) that must first migrate extensively during brain and spinal cord development. We show that OPCs require the vasculature as a physical substrate for migration. We observed that OPCs of the embryonic mouse brain and spinal cord, as well as the human cortex, emerge from progenitor domains and associate with the abluminal endothelial surface of nearby blood vessels. Migrating OPCs crawl along and jump between vessels. OPC migration in vivo was disrupted in mice with defective vascular architecture but was normal in mice lacking pericytes. Thus, physical interactions with the vascular endothelium are required for OPC migration. We identify Wnt-Cxcr4 (chemokine receptor 4) signaling in regulation of OPC-endothelial interactions and propose that this signaling coordinates OPC migration with differentiation.

The temporal and spatial patterning involved in the specification, differentiation, and myelination by oligodendroglia is coordinated in part by the activation and repression of various transcriptional programs. Olig2 is a basic helix-loop-helix transcription factor necessary for oligodendroglial development and expressed continuously throughout the lineage. Despite evidence for the critical role of Olig2 in oligodendroglial specification and differentiation, the function for Olig2 during later stages of oligodendroglial development, namely, the transition into mature oligodendrocytes (OLs) and the formation of the myelin sheath, remains unclear. To address the possibility for a stage-specific role, we deleted Olig2 in oligodendrocyte precursor cells (OPCs) under the control of the CNPase-promoter or in immature OLs under the inducible proteolipid protein promoter. As expected, ablation of Olig2 in OPCs significantly inhibits differentiation, resulting in hypomyelination. However, deletion of the Olig2 gene in immature OLs significantly enhances the maturation process and accelerates the kinetics of myelination/remyelination. Underlying the stage-specific roles for Olig2 is the compensatory expression and function of Olig1, a transcription factor that promotes OL maturation and (re)myelination. Olig1 expression is significantly reduced upon Olig2 deletion in OPCs but is dramatically increased by nearly threefold when deleted in immature OLs. By enforcing expression of Olig1 into OPCs in a null Olig2 background, we demonstrate that overexpression of Olig1 is sufficient to rescue the differentiation phenotype and partially compensates for the Olig2 deletion in vitro. Our results suggest a stage-specific regulatory role for Olig2, mediated by Olig1 that conveys opposing functions on the differentiation and maturation of oligodendrocytes.

Functional screening for compounds that promote remyelination represents a major hurdle in the development of rational therapeutics for multiple sclerosis. Screening for remyelination is problematic, as myelination requires the presence of axons. Standard methods do not resolve cell-autonomous effects and are not suited for high-throughput formats. Here we describe a binary indicant for myelination using micropillar arrays (BIMA). Engineered with conical dimensions, micropillars permit resolution of the extent and length of membrane wrapping from a single two-dimensional image. Confocal imaging acquired from the base to the tip of the pillars allows for detection of concentric wrapping observed as 'rings' of myelin. The platform is formatted in 96-well plates, amenable to semiautomated random acquisition and automated detection and quantification. Upon screening 1,000 bioactive molecules, we identified a cluster of antimuscarinic compounds that enhance oligodendrocyte differentiation and remyelination. Our findings demonstrate a new high-throughput screening platform for potential regenerative therapeutics in multiple sclerosis., Loss of myelin in diseases such as multiple sclerosis results in the disruption of the nerve signal, damage to the axon and, finally, neuro- degeneration. In order to effectively treat [...]

Haloperidol is a commonly used, typical, antipsychotic drug (APD) that acts strongly against positive symptoms, but has fewer therapeutic effects on, or may even aggravate, negative symptoms and cognitive deficits in patients with schizophrenia. Loss of oligodendrocytes has been suggested as a factor associated with the negative symptoms of schizophrenia. Recent study shows that chronic haloperidol treatment induced down-regulation of oligodendrocyte-related genes in certain brain regions of mouse. In this study, we used primary oligodendrocyte progenitor cell cultures from 1- to 3-day-postnatal rats to investigate the direct effects of haloperidol on the proliferation and differentiation of oligodendrocyte progenitor cells. Our results showed that (i) haloperidol (0-10.0 µmol x [L.sup.-1]) facilitated the proliferation of oligodendrocyte progenitor cells, (ii)chronic haloperidol (0.5 µmol x [L.sup.-1]) treatment decreased the number of myelin basic protein positive oligodendrocytes and reduced the oligodendrocytes cells possessing myelin-like membranes, resulting in inhibition of the terminal differentiation of oligodendrocytes, and (iii) D3 receptor mRNA was detected in oligodendrocyte progenitor cells, and haloperidol treatment induced a down-regulation of D3 receptor mRNA. These results suggest that the typical antipsychotic drug haloperidol affects the development of oligodendrocyte progenitor cells, and that D3 receptor down regulation may be involved. Our observations provide new insight into possible cellular mechanisms responsible for the side effects of typical antipsychotic drugs and support the concept that abnormality of oligodendrocytes may be involved in the pathogenesis of schizophrenia. Key words: haloperidol, oligodendrocyte progenitor cell, proliferation, schizophrenia, dopamine receptor. L'haloperidol, un medicament antipsychotique typique, agit fortement contre les symptomes positifs mais exerce moins d'effets theerapeutiques, ou aggrave meme les symptomes negatifs et les deficits cognitifs des patients souffrant de schizophrenie. La perte d'oligodendrocytes a ete suggeree comme facteur associe aux symptomes negatifs de la schizophrenie. Des etudes recentes montrent qu'un traitement chronique a l'haloperidol induisait une diminution de l'expression de genes relies aux oligodendrocytes dans certaines regions du cerveau de la souris. Dans cette etude, nous avons utilise; des cultures primaires de cellules progenitrices d'oligodendrocytes de rats aux jours post-nataux 1-3, pour examiner les effets directs de l'haloperidol sur la proliferation et la differentiation des cellules progenitrices d'oligodendrocytes. Nous resultats ont montre que (i) l'haloperidol (0-10,0 µmol x [L.sup.-1]) facilitait la proliferation des cellules progenitrices d'oligodendrocytes, (ii) un traitement chronique a l'haloperidol (0,5 µmol x [L.sup.-1]) diminuait le nombre d'oligodendrocytes possedant des membranes de type myeline, resultant en une inhibition de la differenciation terminale des oligodendrocytes et (iii) l'ARNm du recepteur D3 etait detecte dans les cellules progenitrices d'oligodendrocytes, et le traitement a l'haloperidol induisait une diminution de l'expression de l'ARNm du recepteur D3. Ces resultats suggerent que l'haloperidol, un medicament antipsychotique typique, affecte le developpement des cellules progenitrices des oligodendrocytes, et que la diminution de l'expression du recepteur D3 pourrait etre impliquee. Nos observations donnent un nouvel apercu des mecanismes cellulaires possiblement responsables des effets secondaires des medicaments antipsychotiques typiques et appuient le concept qu'une anomalie des oligodendrocytes puisse etre impliquee dans la pathogenese de la schizophrenie. Mots-cles: haloperidol, cellule progenitrice d'oligodendrocytes, proliferation, differentiation, schizophrenie, recepteur de la dopamine. [Traduit par la Redaction], Introduction Haloperidol is a commonly used, typical, antipsychotic drug (APD). It has been shown to act strongly against positive symptoms, such as psychoses, hallucinations, and disordered thought processes, likely due [...]

Mitochondrial malfunction associated with impaired mitochondrial quality control and self-renewal machinery, known as mitophagy, is an under-appreciated mechanism precipitating synaptic loss and cognitive impairments in Alzheimer's disease (AD). Promoting mitophagy has been shown to improve cognitive function in AD animals. However, the regulatory mechanism was unclear, which formed the aim of this study. Here, we found that a neuron-specific loss of Bcl-2 family member BOK in AD patients and APPswe/PS1dE9 (APP/PS1) mice is closely associated with mitochondrial damage and mitophagy defects. We further revealed that BOK is the key to the Parkin-mediated mitophagy through competitive binding to the MCL1/Parkin complex, resulting in Parkin release and translocation to damaged mitochondria to initiate mitophagy. Furthermore, overexpressing bok in hippocampal neurons of APP/PS1 mice alleviated mitophagy and mitochondrial malfunction, resulting in improved cognitive function. Conversely, the knockdown of bok worsened the aforementioned AD-related changes. Our findings uncover a novel mechanism of BOK signaling through regulating Parkin-mediated mitophagy to mitigate amyloid pathology, mitochondrial and synaptic malfunctions, and cognitive decline in AD, thus representing a promising therapeutic target., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)