Expression Of Olig2 Research Articles

GPR68 Improves Nerve Damage and Myelination in an Immature Rat Model Induced by Sevoflurane Anesthesia by Activating cAMP/CREB to Mediate BDNF.

Ovarian cancer G-protein-coupled receptor 1 (OGR1, also known as GPR68) is a member of proton-sensing G-protein-coupled receptors, involved in cardiovascular physiology, tumor biology, and asthma, and exerts a neuroprotective effect against brain ischemia. The effects of GPR68 on anesthesia-induced nerve damage and myelination were investigated in this study. First, 2-day old postnatal rats were exposed to 4.9% sevoflurane for 2 h. Data from hematoxylin and eosin staining and Nissl staining showed that sevoflurane induced pathological changes in the hippocampus with a reduced number of neurons. GPR68 was downregulated in the hippocampus of sevoflurane-induced rats. Second, sevoflurane-induced rats were injected with adeno-associated virus (AAV)-mediated overexpression of GPR68, and overexpression of GPR68 ameliorated sevoflurane-induced pathological changes, enhanced the number of neurons, and improved the learning and memory function. Moreover, overexpression of GPR68 increased the number of BrdU-positive and Olig2-positive cells and enhanced protein expression of Olig2 in sevoflurane-induced rats. Third, the number of myelin basic protein (MBP) positive cells and protein expression of MBP in sevoflurane-induced rats were also enhanced by injection with AAV-GPR68. Overexpression of GPR68 attenuated sevoflurane-induced neuronal apoptosis and oxidative stress in rats. Lastly, overexpression of GPR68 upregulated protein expression of the brain-derived neurotrophic factor (BDNF) by increasing cAMP and phosphorylated cAMP response element-binding protein (CREB). In conclusion, GPR68 alleviated sevoflurane-induced nerve damage and myelination through BDNF-mediated activation of the cAMP/CREB pathway.

Sonic Hedgehog Pathway Modulation Normalizes Expression of Olig2 in Rostrally Patterned NPCs With Trisomy 21.

The intellectual disability found in people with Down syndrome is associated with numerous changes in early brain development, including the proliferation and differentiation of neural progenitor cells (NPCs) and the formation and maintenance of myelin in the brain. To study how early neural precursors are affected by trisomy 21, we differentiated two isogenic lines of induced pluripotent stem cells derived from people with Down syndrome into brain-like and spinal cord-like NPCs and promoted a transition towards oligodendroglial fate by activating the Sonic hedgehog (SHH) pathway. In the spinal cord-like trisomic cells, we found no difference in expression of OLIG2 or NKX2.2, two transcription factors essential for commitment to the oligodendrocyte lineage. However, in the brain-like trisomic NPCs, OLIG2 is significantly upregulated and is associated with reduced expression of NKX2.2. We found that this gene dysregulation and block in NPC transition can be normalized by increasing the concentration of a SHH pathway agonist (SAG) during differentiation. These results underscore the importance of regional and cell type differences in gene expression in Down syndrome and demonstrate that modulation of SHH signaling in trisomic cells can rescue an early perturbed step in neural lineage specification.

Shh and Olig2 sequentially regulate oligodendrocyte differentiation from hiPSCs for the treatment of ischemic stroke.

Rationale: Demyelination is a major component of white matter injury, characterized by oligodendrocyte (OL) death and myelin sheath loss, which result in memory loss and cognitive impairment in the context of ischemic stroke. Accumulating evidence has shown that OLs can be generated by the direct activation of defined transcription factors (TFs) in human induced pluripotent stem cells (hiPSCs); however, the rapid acquisition of single TF-induced OL progenitor cells (OPCs) as cell therapy for ischemic stroke remains to be thoroughly explored.Methods: A stable, chemically defined protocol was used to generate a substantial number of transplantable and functional OLs through the partial inhibition of sonic hedgehog (Shh) activity by GANT61 during neural induction from hiPSCs and sequential induction of TF Olig2 overexpression. Transcriptome and metabolome analyses further revealed a novel molecular event in which Olig2 regulates OL differentiation from hiPSC-derived neural progenitor cells (NPCs). Olig2-induced NG2+ OPCs (Olig2-OPCs) were then evaluated for their therapeutic potential in cell-based therapy for ischemic stroke.Results: GANT61 treatment resulted in a motor neuron (MN)-OL fate switch during neural induction, and induced overexpression of Olig2 accelerated oligodendroglial lineage cell specification. Olig2-OPCs expressed typical oligodendroglial lineage marker genes, including NKX2.2, CSPG4, and ST8SIA1, and displayed superior ability to differentiate into mature OLs in vitro. Mechanistically, Olig2-OPCs showed increased gene expression of the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway, and activated CEPT1-mediated phospholipogenesis. Functionally, inhibiting PPARγ and knocking down CEPT1 further compromised the terminal differentiation of Olig2-OPCs. Most importantly, when transplanted into a rat model of transient middle cerebral artery occlusion (tMCAO), Olig2-OPCs efficiently promoted neurological functional recovery by reducing neuronal death, promoting remyelination, and rescuing spatial memory decline.Conclusions: We developed a stable, chemically defined protocol to generate OPCs/OLs with partial inhibition of Shh activity by GANT61 from hiPSCs and sequentially induced the expression of the single TF Olig2. Olig2-OPC transplantation may be an ideal alternative approach for ischemic stroke rehabilitation therapy.

The Shh/Gli1 signaling pathway regulates regeneration via transcription factor Olig1 expression after focal cerebral ischemia in rats

ABSTRACT Objective Ischemic stroke is a major cause of death in the global population, with a high disability and mortality rate. Lack of regenerative ability is considered to be the fundamental cause. This study aims to determine the effect of Shh pathway, which mediates regenerative signaling in response to CNS injury, on myelin repair and Olig1 expression in focal ischemic lesions in the rat. Methods A model of middle cerebral artery occlusion (MCAO) was established using the intraluminal suture method where the middle cerebral artery (MCA) was restricted for 120 min. Cyclopamine, a specific inhibitor of Shh, or saline was administered 12h after MCAO surgery and lasted for 7d. After MCA occlusion, male Sprague-Dawley rats were randomly allocated to cyclopamine- or saline-treated groups. A group of no-injection animals after MCAO were used as control. The Shh signaling pathway, myelinogenesis-related factor MBP and Olig1 were tested using immunohistochemistry and RT-PCR assay. Results The levels of Shh and its component Gli1 were elevated from 1d up to 14d following ischemia, indicating that the Shh-Gli1 axis was broadly reactivated. Treatment with cyclopamine can partially block the Shh signaling pathway, prevent myelin repair, and decrease the Olig1 expression following ischemic stroke. Conclusion That blockade of Shh signaling concurrently with the creation of a lesion aggravated ischemic myelin damage, probably via its downstream effects on Olig1 transcription. Shh plays a contributory role during regeneration in the CNS, thereby providing promising new therapeutic strategies to assist in recovery from ischemic stroke.

Diffuse leptomeningeal glioneuronal tumour (DLGNT) in children: the emerging role of genomic analysis

Diffuse leptomeningeal glioneuronal tumours (DLGNT) represent rare enigmatic CNS tumours of childhood. Most patients with this disease share common radiological and histopathological features but the clinical course of this disease is variable. A radiological hallmark of this disease is widespread leptomeningeal enhancement that may involve the entire neuroaxis with predilection for the posterior fossa and spine. The classic pathologic features include low- to moderate-density cellular lesions with OLIG2 expression and evidence of ‘oligodendroglioma-like’ appearance. The MAPK/ERK signaling pathway has recently been reported as a potential driver of tumourigenesis in up to 80% of DLGNT with KIAA1549:BRAF fusions being the most common event seen. Until now, limited analysis of the biological drivers of tumourigenesis has been undertaken via targeted profiling, chromosomal analysis and immunohistochemistry. Our study represents the first examples of comprehensive genomic sequencing in DLGNT and shows that it is not only feasible but crucial to our understanding of this rare disease. Moreover, we demonstrate that DLGNT may be more genomically complex than single-event MAPK/ERK signaling pathway tumours.

Levetiracetam promoted rat embryonic neurogenesis via NMDA receptor-mediated mechanism in vitro

AimsLevetiracetam (LEV) is a broad-spectrum antiepileptic drug with neuroprotective properties and novel mechanisms of action. Some evidence suggests that LEV may impact adult neurogenesis, but the results are controversial. The present study was aimed to evaluate the effects of LEV on the proliferation and differentiation of rat embryonic neural stem cells (NSCs) and to explore the role of GABAB or NMDA receptors. Main methodsNSCs were isolated from rat fetal ganglionic eminence at embryonic day 14.5. The effects of LEV on viability, proliferation, neurosphere formation, and neuronal or astroglial differentiation of NSCs were assessed using resazurin, BrdU incorporation, immunocytochemistry, quantitative real-time PCR, and western blotting. Additionally, we addressed the relationship between treatment with NMDA and GABAB receptor antagonists (MK801 and saclofen, respectively) in combination with LEV on these parameters. Key findingsThe data showed that LEV (50 μM) significantly increased the number (p < 0.01) and diameter of neurospheres (p < 0.05), enhanced proliferation (p < 0.01), and promoted neuronal differentiation, as revealed by significantly increased expressions of DCX and NeuN. The expressions of astroglial markers, GFAP and Olig2, were markedly reduced. The addition of MK801 (10 μM) significantly diminished neurospheres growth (p < 0.001), decreased the number of proliferating cells (p < 0.01), and reduced the number of new neurons (p < 0.001) but increased the astroglial cells (p < 0.001) induced by LEV. Co-treatment with saclofen (25 μM) did not significantly affect LEV-induced NSCs proliferation and differentiation. SignificanceOur findings suggest that LEV may enhance rat embryonic neurogenesis mainly through an NMDA receptor-mediated mechanism.

Derivation of Oligodendrocyte Precursors from Adult Bone Marrow Stromal Cells for Remyelination Therapy.

Transplantation of oligodendrocyte precursors (OPs) is potentially therapeutic for myelin disorders but a safe and accessible cell source remains to be identified. Here we report a two-step protocol for derivation of highly enriched populations of OPs from bone marrow stromal cells of young adult rats (aMSCs). Neural progenitors among the aMSCs were expanded in non-adherent sphere-forming cultures and subsequently directed along the OP lineage with the use of glial-inducing growth factors. Immunocytochemical and flow cytometric analyses of these cells confirmed OP-like expression of Olig2, PDGFRα, NG2, and Sox10. OPs so derived formed compact myelin both in vitro, as in co-culture with purified neurons, and in vivo, following transplantation into the corpus callosum of neonatal shiverer mice. Not only did the density of myelinated axons in the corpus callosum of recipient shiverer mice reach levels comparable to those in age-matched wild-type mice, but the mean lifespan of recipient shiverer mice also far exceeded those of non-recipient shiverer mice. Our results thus promise progress in harnessing the OP-generating potential of aMSCs towards cell therapy for myelin disorders.

Analysis of platelet-derived growth factor receptor A and oligodendrocyte transcription factor 2 markers following Hydroxychloroquine administration in animal induced multiple sclerosis model.

It has been shown that following demyelination, Oligodendrocyte Progenitor Cells (OPCs) migrate to the lesion site and begin to proliferate, and differentiate. This study aimed to investigate the effects of Hydroxychloroquine (HCQ) on the expression of OLIG-2 and PDGFR-α markers during the myelination process. C57BL/6 mice were fed cuprizone pellets for 5weeks to induce demyelination and return to a normal diet for 1week to stimulate remyelination. During the Phase I all of the animals except CPZ and Vehicle groups were exposed to HCQ (2.5, 10, and 100mg/kg) via drinking water. At the end of the study, animals were euthanized, perfused and the brain samples were assessed for myelination and immunohistochemistry evaluation. What is remarkable is the high rate of Olig2 + cells in the groups treated with 10 and 100mg/kg HCQ in the demyelination phase and its decreasing trend in the remyelination phase. However, there was no significant difference between groups during phase I and Phase II based on the percentage of olig-2+/total cells in the corpus callosum region. The number of PDGFR-α+ cells in the group treated with 10mg/kg HCQ was significant in the first phase (p value < 0.05). Considering that the 100mg/kg HCQ group had the highest level of PDGFR-α as well as the highest level of myelin repair in LFB staining, it could be inferred that it was the most effective dose in inducing proliferation and migration of OPCs.

ME2 Promotes Proneural-Mesenchymal Transition and Lipogenesis in Glioblastoma.

Malic enzyme 2 (ME2) catalyzes the formation of pyruvate from malic acid and is abnormally expressed in some tumors. However, the exact effects of ME2 on proneural–mesenchymal transition (PMT) and lipogenesis in glioblastoma multiforme (GBM) remain unexplored. Here, we found that ME2 expression was significantly higher in GBM than in normal brain tissues and negatively correlated with overall survival of patients with GBM. Furthermore, we demonstrated that ME2 was positively correlated with mesenchymal features in GBM and promoted proliferation, migration, and invasion of glioma cells. Moreover, ME2 upregulated the expression of mesenchymal markers (N-cadherin, vimentin, YKL40, and MET), whereas it inhibited the expression of proneural maker OLIG2, indicating that ME2 might promote PMT in GBM. We also found that ME2 inhibited the production of mitochondrial reactive oxygen species and AMPK phosphorylation, resulting in SREBP-1 maturation and nuclear localization and enhancing the ACSS2 lipogenesis pathway. Taken together, these results suggest that ME2 promotes PMT and is linked with reprogramming of lipogenesis via AMPK–SREBP-1–ACSS2 signaling in GBM. Therefore, ME2 has potential as a new classification marker in GBM and could provide a new approach to glioma treatment.

Transcriptome profiling of the Olig2-expressing astrocyte subtype reveals their unique molecular signature

SummaryAstrocytes are recognized to be a heterogeneous population of cells that differ morphologically, functionally, and molecularly. Whether this heterogeneity results from generation of distinct astrocyte cell lineages, each functionally specialized to perform specific tasks, remains an open question. In this study, we used RNA sequencing analysis to determine the global transcriptome profile of the Olig2-expressing astrocyte subtype (Olig2-AS), a specific spinal astrocyte subtype that segregates early during development from Olig2 progenitors and differs from other spinal astrocytes by the expression of Olig2. We identified 245 differentially expressed genes. Among them, 135 exhibit higher levels of expression when compared with other populations of spinal astrocytes, indicating that these genes can serve as a “unique” functional signature of Olig2-AS. Among them, we identify two genes, inka2 and kcnip3, as specific molecular markers of the Olig2-AS in the P7 spinal cord. Our work thus reveals that Olig2 progenitors produce a unique spinal astrocyte subtype.

Shenzhiling oral liquid protects the myelin sheath against Alzheimer's disease through the PI3K/Akt-mTOR pathway

Ethnopharmacological relevanceShenzhiling oral liquid (SZL), a traditional Chinese medicine (TCM) compound, is firstly approved by the Chinese Food and Drug Administration (CFDA) for the treatment of mild to moderate Alzheimer's disease (AD). SZL is composed of ten Chinese herbs, and the precise therapy mechanism of its action to AD is far from fully understood. Aim of the studyThe purpose of this study was to observe whether SZL is an effective therapy for amyloid-beta (Aβ)-induced myelin sheath and oligodendrocytes impairments. Notably, the primary aim was to elucidate whether and through what underlying mechanism SZL protects the myelin sheath through the PI3K/Akt-mTOR signaling pathway in Aβ42-induced OLN-93 oligodendrocytes in vitro. Materials and methodsAPP/PS1 mice were treated with SZL or donepezil continuously for three months, and Aβ42-induced oligodendrocyte OLN-93 cells mimicking AD pathogenesis of myelin sheath impairments were incubated with SZL-containing serum or with donepezil. LC-MS/MS was used to analysis the active components of SZL and SZL-containing serum. The Y maze test was administered after 3 months of treatment, and the hippocampal tissues of the APP/PS1 mice were then harvested for observation of myelin sheath and oligodendrocyte morphology. Cell viability and toxicity were assessed using CCK-8 and lactate dehydrogenase (LDH) release assays, and flow cytometry was used to measure cell apoptosis. The expression of the myelin proteins MBP, PLP, and MAG and that of Aβ42 and Aβ40 in the hippocampi of APP/PS1 mice were examined after SZL treatment. Simultaneously, the expression of p-PI3K, PI3K, p-Akt, Akt, p-mTOR, and mTOR were also examined. The expression of proteins, including CNPase, Olig2, NKX2.2, MBP, PLP, MAG, MOG, p-PI3K, PI3K, p-Akt, Akt, p-mTOR, and mTOR, was determined by immunofluorescence and Western blot, and the corresponding gene expression was evaluated by qPCR in Aβ42-induced OLN-93 oligodendrocytes. ResultsLC-MS/MS detected a total of 126 active compounds in SZL-containing serum, including terpenoids, flavones, phenols, phenylpropanoids and phenolic acids. SZL treatment significantly improved memory and cognition in APP/PS1 mice and decreased the G-ratio of myelin sheath, alleviated myelin sheath and oligodendrocyte impairments by decreasing Aβ42 and Aβ40 accumulation and increasing the expression of myelin proteins MBP, PLP, MAG, and PI3K/Akt-mTOR signaling pathway associated protein in the hippocampi of APP/PS1 mice. SZL-containing serum also significantly reversed the OLN-93 cell injury induced by Aβ42 by increasing cell viability and enhanced the expression of MBP, PLP, MAG, and MOG. Meanwhile, SZL-containing serum facilitated the maturation and differentiation of oligodendrocytes in Aβ42-induced OLN-93 cells by heightening the expression of CNPase, Olig2 and NKX2.2. SZL-containing serum treatment also fostered the expression of p-PI3K, PI3K, p-Akt, Akt, p-mTOR, and mTOR, indicating an activating PI3K/Akt-mTOR signaling pathway in OLN-93 cells. Furthermore, the effects of SZL on myelin proteins, p-Akt, and p-mTOR were clearly inhibited by LY294002 and/or rapamycin, antagonists of PI3K and m-TOR, respectively. ConclusionsOur findings indicate that SZL exhibits a neuroprotective effect on the myelin sheath by promoting the expression of myelin proteins during AD, and its mechanism of action is closely related to the activation of the PI3K/Akt-mTOR signaling pathway.

EMBR-02. OLIG2 REPRESENTS A PROGNOSTIC MARKER AND THERAPEUTIC TARGET IN MYC-AMPLIFIED MEDULLOBLASTOMA RELAPSE AND METASTASIS

Medulloblastoma (MB) is one of the most common malignant pediatric brain tumors. Among the multiple MB subtypes, MB with MYC amplification confers an extremely poor prognosis with an overall survival rate of less than 30%. Relapse is often mediated by a small population of therapy-resistant tumor cells which expand and ultimately progress to lethal tumors. Moreover, MYC-amplified MB exhibits a high incidence of leptomeningeal metastases. Approximately one-third of patients with MYC-amplified MB present with metastases and nearly all have this complication at relapse. Metastatic MYC-amplified MB is highly fatal. As such, our ability to effectively treat MYC-amplified MB is largely dependent on our capacity to eradicate the therapy resistant tumor cells, particularly the metastatic tumor cells. The development of clinically effective therapies for this disease will be facilitated by the identification of therapy-resistant tumor cell populations and their molecular signatures involved in tumor metastasis and relapse. Using patient-derived xenograft (PDX) mouse models, we recently discovered that a subset of MYC-amplified MB tumors with strong OLIG2 expression (OLIG2-high) is resistant to radiation and prone to metastasize, whereas MYC-amplified MB tumors without OLIG2 expression (OLIG2-low) are sensitive to radiation without dissemination. Irradiation of OLIG2-high tumors led to either a small number of quiescent OLIG2- cancer stem-like cells (CSLCs) remaining in the cerebellar bed or to the dissemination of highly proliferative OLIG2+ tumor cells along the leptomeninges. All mice harboring these radioresistant CSLCs succumbed to relapse. Further studies demonstrated that the quiescent OLIG2- CSLCs did not contribute to tumor recurrence directly, while elimination of OLIG2+ radioresistant CSLCs with a small molecule OLIG2 antagonist significantly prevented metastatic recurrence, delayed tumor growth and prolonged animal survival. Thus, our studies provide new insights into the role of OLIG2 in radiotherapy resistance and metastasis in MYC-amplified MB and propose a novel therapeutic approach to treating metastatic MYC-amplified MB.

HGG-43. INTERROGATING THE ROLE OF PEA3 ONCOGENIC TRANSCRIPTION FACTORS IN PEDIATRIC HIGH-GRADE K27M GLIOMAS

Pediatric high-grade gliomas (HGGs) are an aggressive form of pediatric brain tumors which pose a grim five-year survival with little advancement in therapeutic efficacy, often requiring a multimodal therapeutic combination of chemotherapy, resection, and radiation. We have previously shown that proper function of ETS transcription factors is necessary for gliomagenesis in Ras/MAPK-driven pediatric gliomas. It is our hypothesis that ETS transcription factors are necessary for tumor initiation in HGGs by promoting the necessary glial cell fates in glioma. Further, we hypothesize that functional inhibition of ETS proteins following tumor formation will improve survival and outcome in HGG. Functional inhibition of ETS proteins using a competitive dominant-negative mutant was shown to completely rescue neural stem cell depletion, tumor formation and tumor-free survival in two rodent models of HGGs. Mechanistically, we show evidence that Pea3 factors may induce glial-cell fate by promoting Olig2 expression and activation of glial transcriptional programs. Indeed, transcriptomic analysis of ETS-perturbed HGG tumors revealed that Sox9 and Olig2 transcription factor networks were dependent on proper ETS function. Further, we show evidence that Etv5 can directly interact with promoter regions of glial fate master regulators in human primary glioma cell lines. To empirically determine the effect of Pea3 proteins on tumorigenesis, we have created a novel methodology for inducible gain- and loss-of-function genetic interrogation of these factors in vivo. Our survival results and combined single-cell RNA-sequencing of individual groups show that inhibition of the Pea3 family leads to a marked increase in survival in K27M glioma by regulating key features of glioblasts. All in all, our group provides evidence that the ETS family of transcription factors is necessary for glial specification of tumor cells and induce pro-glial transcriptional programs by activating OPC- and astrocyte-specific genes in K27M-driven tumors.

Impact of the Olig Family on Neurodevelopmental Disorders.

The Olig genes encode members of the basic helix-loop-helix (bHLH) family of transcription factors. Olig1, Olig2, and Olig3 are expressed in both the developing and mature central nervous system (CNS) and strictly regulate cellular specification and differentiation. Extensive studies have established functional roles of Olig1 and Olig2 in directing neuronal and glial formation during different stages in development. Recently, Olig2 overexpression was implicated in neurodevelopmental disorders down syndrome (DS) and autism spectrum disorder (ASD) but its influence on cognitive and intellectual defects remains unknown. In this review, we summarize the biological functions of the Olig family and how it uniquely promotes cellular diversity in the CNS. This is followed up with a discussion on how abnormal Olig2 expression impacts brain development and function in DS and ASD. Collectively, the studies described here emphasize vital features of the Olig members and their distinctive potential roles in neurodevelopmental disease states.

One-step Reprogramming of Human Fibroblasts into Oligodendrocyte-like Cells by SOX10, OLIG2, and NKX6.2.

SummaryLimited access to human oligodendrocytes impairs better understanding of oligodendrocyte pathology in myelin diseases. Here, we describe a method to robustly convert human fibroblasts directly into oligodendrocyte-like cells (dc-hiOLs), which allows evaluation of remyelination-promoting compounds and disease modeling. Ectopic expression of SOX10, OLIG2, and NKX6.2 in human fibroblasts results in rapid generation of O4+ cells, which further differentiate into MBP+ mature oligodendrocyte-like cells within 16 days. dc-hiOLs undergo chromatin remodeling to express oligodendrocyte markers, ensheath axons, and nanofibers in vitro, respond to promyelination compound treatment, and recapitulate in vitro oligodendroglial pathologies associated with Pelizaeus-Merzbacher leukodystrophy related to PLP1 mutations. Furthermore, DNA methylome analysis provides evidence that the CpG methylation pattern significantly differs between dc-hiOLs derived from fibroblasts of young and old donors, indicating the maintenance of the source cells’ “age.” In summary, dc-hiOLs represent a reproducible technology that could contribute to personalized medicine in the field of myelin diseases.

Quetiapine promotes oligodendroglial process outgrowth and membrane expansion by orchestrating the effects of Olig1.

Oligodendroglial lineage cells go through a series of morphological changes before myelination. Prior to myelination, cell processes and membrane structures enlarge by approximately 7,000 times, which is required to support axonal wrapping and myelin segment formation. Failure of these processes leads to maldevelopment and impaired myelination. Quetiapine, an atypical antipsychotic drug, was proved to promote oligodendroglial differentiation and (re)myelination, pending detailed effects and regulatory mechanism. In this study, we showed that quetiapine promotes morphological maturation of oligodendroglial lineage cells and myelin segment formation, and a short-term quetiapine treatment is sufficient to induce these changes. To uncover the underlying mechanism, we examined the effect of quetiapine on the Oligodendrocyte transcription factor 1 (Olig1). We found that quetiapine upregulates Olig1 expression level and promotes nuclear Olig1 translocation to the cytosol, where it functions not as a transcription modulator, but in a way that highly correlates with oligodendrocyte morphological transformation. In addition, quetiapine treatment reverses the negative regulatory effect of the Olig1-regulated G protein-coupled receptor 17 (GPR17) on oligodendroglial morphological maturation. Our results demonstrate that quetiapine enhances oligodendroglial differentiation and myelination by promoting cell morphological transformation. This would shed light on the orchestration of oligodendroglia developmental mechanisms, and provides new targets for further therapeutic research.

Region-specific distribution of Olig2-expressing astrocytes in adult mouse brain and spinal cord

Olig2 is an important transcription factor essential for the specification and differentiation of oligodendrocytes as well as astrocytes and neurons during developmental stages. However, Olig2 distribution pattern and its relationship among different types of glial cells in the adult central nervous system (CNS) are not well characterized. Here, we systematically examined Olig2 expression pattern in combination with major markers of neurons and glial cells throughout the brain and spinal cord in the adult mice. As expected, Olig2 is universally expressed in oligodendrocytes and oligodendrocyte precursor cells (OPCs), but not in neurons or microglia. Interestingly, we discover a subpopulation of Olig2+ astrocytes that are highly enriched in some specific regions including the olfactory bulb, thalamus, midbrain, medulla, and spinal cord in the adult mice. Moreover, OPCs have high expression level of Olig2, whereas oligodendrocytes and astrocytes have similar level of Olig2 expression. Our results suggest that a distinct population of Olig2+ astrocytes are highly concentrated in discrete regions in the adult CNS. Investigating the functional significance of these Olig2+ astrocytes in both resting state and pathological state of the brain and spinal cord may broaden our understanding on astrocytic heterogeneity and functions.

Direct reprogramming of oligodendrocyte precursor cells into GABAergic inhibitory neurons by a single homeodomain transcription factor Dlx2

Oligodendrocyte precursor cells (NG2 glia) are uniformly distributed proliferative cells in the mammalian central nervous system and generate myelinating oligodendrocytes throughout life. A subpopulation of OPCs in the neocortex arises from progenitor cells in the embryonic ganglionic eminences that also produce inhibitory neurons. The neuronal fate of some progenitor cells is sealed before birth as they become committed to the oligodendrocyte lineage, marked by sustained expression of the oligodendrocyte transcription factor Olig2, which represses the interneuron transcription factor Dlx2. Here we show that misexpression of Dlx2 alone in postnatal mouse OPCs caused them to switch their fate to GABAergic neurons within 2 days by downregulating Olig2 and upregulating a network of inhibitory neuron transcripts. After two weeks, some OPC-derived neurons generated trains of action potentials and formed clusters of GABAergic synaptic proteins. Our study revealed that the developmental molecular logic can be applied to promote neuronal reprogramming from OPCs.

Effects of Nanoplastics and Butyl Methoxydibenzoylmethane on Early Zebrafish Embryos Identified by Single-Cell RNA Sequencing.

Nanoplastics with small particle sizes and high surface area/volume ratios easily absorb environmental pollutants and affect their bioavailability. In this study, polystyrene nanoplastic beads (PS-NPBs) with a particle size of 100 nm and butyl methoxydibenzoylmethane (BMDBM) sunscreen in personal-care products were chosen as target pollutants to study their developmental toxicity and interactive effects on zebrafish embryos. The exposure period was set from 2 to 12 h postfertilization (hpf). BMDBM and PS-NPBs significantly upregulated genes related to antioxidant enzymes and downregulated the gene expression of aromatase and DNA methyltransferases, but the influenced genes were not exactly the same. The combined exposure reduced the adverse effects on the expression of all genes. With the help of the single-cell RNA sequencing technology, neural mid cells were identified as the target cells of both pollutants, and brain development, head development, and the notch signaling pathway were the functions they commonly altered. The key genes and functions that are specifically affected by BMDBM and/or PS-NPBs were identified. BMDBM mainly affects the differentiation and fate of neurons in the central nervous system through the regulation of her5, her6, her11, lfng, pax2a, and fgfr4. The PS-NPBs regulate the expression of olig2, foxg1a, fzd8b, six3a, rx1, lhx2b, nkx2.1a, and sfrp5 to alter nervous system development, retinal development, and stem cell differentiation. The phenotypic responses of zebrafish larvae at 120 hpf were tested, and significant inhibition of locomotor activity was found, indicating that early effects on the central nervous system would have a sustained impact on the behavior of zebrafish.

Immunohistochemical expression of Olig2, CD99, and EMA to differentiate oligodendroglial-like neoplasms.

This study has assessed the diagnostic ability of oligodendrocyte-2 (Olig2), CD99, and epithelial membrane antigen (EMA) immunohistochemical stains to diagnose oligodendroglial-like neoplasms as central neurocytoma, ependymoma, or oligodendroglioma. An immunohistochemistry (IHC) panel of Olig2, EMA, and CD99 was performed on 18 central neurocytomas, 46 ependymomas, and 28 oligodendrogliomas. Aquantitative labelling index of stained tumor cells was assessed using ascoring system, and its diagnostic predictability was evaluated with multinomial logistic regression. Significant differences in IHC expression patterns were observed between all tumor groups (p < 0.001). The labeling indices of the histochemical expression of Olig2, EMA, and CD99 were related to diagnostic predictability. Olig2 was unlikely to differentiate ependymoma from central neurocytoma (p = 0.154), while EMA and CD99 were significant in diagnosing these two tumors (p < 0.05). Olig2 was aspecific marker of oligodendroglioma, differentiating it from ependymoma and central neurocytoma (p 0.05), but CD99 significantly differentiated ependymoma from oligodendroglioma (p = 0.022). These labelling indices were used to re-assess the diagnostic accuracy, regardless of tumor location and histology, and yielded significantly different tumor diagnoses. The IHC panel of Olig2, EMA, and CD99 should be used to differentiate oligodendroglial-like neoplasms. Olig2 is aspecific IHC marker to diagnose oligodendroglioma and differentiate it from ependymoma and central neurocytoma. Lack of Olig2 expression rules out oligodendroglioma and suggests the diagnosis of ependymoma rather than central neurocytoma if the EMA labelling index shows diffuse/partial expression. CD99 is considered asensitive marker for ependymoma but not central neurocytoma.