Astrocyte maturation is crucial for brain function,yet the mechanisms regulating this process remain poorly understood.In this study,we identify the bHLH transcription factors Olig1 and Olig2 as essential coordinators...Astrocyte maturation is crucial for brain function,yet the mechanisms regulating this process remain poorly understood.In this study,we identify the bHLH transcription factors Olig1 and Olig2 as essential coordinators of cortical astrocyte maturation.We demonstrate that Olig1 and Olig2 work synergistically to regulate cortical astrocyte maturation by modulating Bmp7 expression.Genetic ablation of both Olig1 and Olig2 results in defective astrocyte morphology,including reduced process complexity and an immature gene expression profile.Single-cell RNA sequencing reveals a shift towards a less mature astrocyte state,marked by elevated levels of HOPX and GFAP,resembling human astrocytes.Mechanistically,Olig1 and Olig2 bind directly to the Bmp7 enhancer,repressing its expression to promote astrocyte maturation.Overexpression of Bmp7 in vivo replicates the astrocyte defects seen in Olig1/2 double mutants,confirming the critical role of BMP7 signaling in this process.These findings provide insights into the transcriptional and signaling pathways regulating astrocyte development and highlight Olig1 and Olig2 as key regulators of cortical astrocyte maturation,with potential implications for understanding glial dysfunction in neurological diseases.展开更多
Oligodendrocytes are the myelinating cells of the central nervous system.Brain injury and neurodegenerative disease often lead to oligodendrocyte death and subsequent demyelination-related pathological changes,resulti...Oligodendrocytes are the myelinating cells of the central nervous system.Brain injury and neurodegenerative disease often lead to oligodendrocyte death and subsequent demyelination-related pathological changes,resulting in neurological defects and cognitive impairment(Spaas et al.,2021;Zhang J et al.,2022).Multiple sclerosis(MS)is a major demyelinating disease of the central nervous system.展开更多
Investigating neural stem cell plasticity in the hippo-campal niche, we demonstrate that retroviral forced expression of Mash1 (Mammalian Achaete-Scute Homolog 1), Olig1(Oligodendrocyte transcription factor 1), and Ol...Investigating neural stem cell plasticity in the hippo-campal niche, we demonstrate that retroviral forced expression of Mash1 (Mammalian Achaete-Scute Homolog 1), Olig1(Oligodendrocyte transcription factor 1), and Olig2 (Oligodendrocyte transcription factor 2) genes, transcription factors involved in enhanced oligodendrogenesis, can contribute to directing the differentiation of adult subventricular zone neural stem cells to functional oligodendrocytes. We found that Mash1, Olig1 and Olig2 all induced oligodendrocyte differentiation. However, Olig1 and Olig2 induction resulted in an elevated number of generated oligoden-drocytes without a significant production of other cell lineages, unlike Mash1. These newly differentiated cells are also capable of migration and possible myelination, showing that targeting oligodendrocyte production and possible remyelination is a viable therapeutic strategy for restoration of neuronal function.展开更多
Neural cell differentiation and maturation is a critical step during central nervous system devel-opment. The oligodendrocyte transcription family （Olig family） is known to be an important factor in regulating neura...Neural cell differentiation and maturation is a critical step during central nervous system devel-opment. The oligodendrocyte transcription family （Olig family） is known to be an important factor in regulating neural cell differentiation. Because of this, the Olig family also affects acute and chronic central nervous system diseases, including brain injury, multiple sclerosis, and even gliomas. Improved understanding about the functions of the Olig family in central nervous system development and disease will greatly aid novel breakthroughs in central nervous system diseases. This review investigates the role of the Olig family in central nervous system develop- ment and related diseases.展开更多
The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions o...The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1 L(myelin transcription factor 1-like), mainly expressed in neurons,has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1 L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1 L in neuron/glia antigen 2-positive(NG2+)OPCs was significantly higher than that in mature CC1+oligodendrocytes. In primary cultured OPCs,overexpression of Myt1 L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1 L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. Ch IP assays showed that Myt1 L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1 L is an essential regulator of OPC differentiation, thereby supporting Myt1 L as a potential therapeutic target for demyelinating diseases.展开更多
Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and my...Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and myelin in serious mental illnesses. However, whether these deficits contribute to the brain dysfunction or pathogenesis of such diseases still lacks direct evidence. In this study, we conditionally deleted Olig2 in oligodendroglial lineage cells (Olig2 cKO) and screened the behavioral changes in adult mice. We found that Olig2 ablation impaired myelin development, which further resulted in severe hypomyelination in the anterior cingulate cortex. Strikingly, Olig2 cKO mice exhibited an anxious phenotype, aberrant responses to stress, and cognitive deficits. Moreover, Olig2 cKO mice showed increased vulnerability to social avoidance under the mild stress of social isolation. Together,these results indicate that developmental deficits in OL and myelin lead to cognitive impairment and increase the risk of phenotypes reminiscent of mental illnesses.展开更多
基金supported by the National Natural Science Foundation of China(82271197,81974175,31820103006,32070971,32200792,32200776).
文摘Astrocyte maturation is crucial for brain function,yet the mechanisms regulating this process remain poorly understood.In this study,we identify the bHLH transcription factors Olig1 and Olig2 as essential coordinators of cortical astrocyte maturation.We demonstrate that Olig1 and Olig2 work synergistically to regulate cortical astrocyte maturation by modulating Bmp7 expression.Genetic ablation of both Olig1 and Olig2 results in defective astrocyte morphology,including reduced process complexity and an immature gene expression profile.Single-cell RNA sequencing reveals a shift towards a less mature astrocyte state,marked by elevated levels of HOPX and GFAP,resembling human astrocytes.Mechanistically,Olig1 and Olig2 bind directly to the Bmp7 enhancer,repressing its expression to promote astrocyte maturation.Overexpression of Bmp7 in vivo replicates the astrocyte defects seen in Olig1/2 double mutants,confirming the critical role of BMP7 signaling in this process.These findings provide insights into the transcriptional and signaling pathways regulating astrocyte development and highlight Olig1 and Olig2 as key regulators of cortical astrocyte maturation,with potential implications for understanding glial dysfunction in neurological diseases.
基金supported by the Zhejiang Provincial Nat ural Science Foundation of China(Nos.LQ21H090016 and LTGY23H090016)。
文摘Oligodendrocytes are the myelinating cells of the central nervous system.Brain injury and neurodegenerative disease often lead to oligodendrocyte death and subsequent demyelination-related pathological changes,resulting in neurological defects and cognitive impairment(Spaas et al.,2021;Zhang J et al.,2022).Multiple sclerosis(MS)is a major demyelinating disease of the central nervous system.
文摘Investigating neural stem cell plasticity in the hippo-campal niche, we demonstrate that retroviral forced expression of Mash1 (Mammalian Achaete-Scute Homolog 1), Olig1(Oligodendrocyte transcription factor 1), and Olig2 (Oligodendrocyte transcription factor 2) genes, transcription factors involved in enhanced oligodendrogenesis, can contribute to directing the differentiation of adult subventricular zone neural stem cells to functional oligodendrocytes. We found that Mash1, Olig1 and Olig2 all induced oligodendrocyte differentiation. However, Olig1 and Olig2 induction resulted in an elevated number of generated oligoden-drocytes without a significant production of other cell lineages, unlike Mash1. These newly differentiated cells are also capable of migration and possible myelination, showing that targeting oligodendrocyte production and possible remyelination is a viable therapeutic strategy for restoration of neuronal function.
基金the National Natural Science Foundation of China,No.81171859the Natural Science Foundation of Chongqing,No.cstc2012jjA10058the Chongqing Health Bureau Project,No.2011-2-172
文摘Neural cell differentiation and maturation is a critical step during central nervous system devel-opment. The oligodendrocyte transcription family （Olig family） is known to be an important factor in regulating neural cell differentiation. Because of this, the Olig family also affects acute and chronic central nervous system diseases, including brain injury, multiple sclerosis, and even gliomas. Improved understanding about the functions of the Olig family in central nervous system development and disease will greatly aid novel breakthroughs in central nervous system diseases. This review investigates the role of the Olig family in central nervous system develop- ment and related diseases.
基金supported by the International Cooperation and Exchange Program of the National Natural Science Foundation of China(81461138035)the National Natural Science Foundation of China(81371326,31571066,and 31371068)+2 种基金the National Basic Research Development Program of China(2016YFA0100802)the UK Medical Research Council(MR/M010503/1)the UK Multiple Sclerosis Society(33)
文摘The differentiation and maturation of oligodendrocyte precursor cells(OPCs) is essential for myelination and remyelination in the CNS. The failure of OPCs to achieve terminal differentiation in demyelinating lesions often results in unsuccessful remyelination in a variety of human demyelinating diseases. However, the molecular mechanisms controlling OPC differentiation under pathological conditions remain largely unknown. Myt1 L(myelin transcription factor 1-like), mainly expressed in neurons,has been associated with intellectual disability, schizophrenia, and depression. In the present study, we found that Myt1 L was expressed in oligodendrocyte lineage cells during myelination and remyelination. The expression level of Myt1 L in neuron/glia antigen 2-positive(NG2+)OPCs was significantly higher than that in mature CC1+oligodendrocytes. In primary cultured OPCs,overexpression of Myt1 L promoted, while knockdown inhibited OPC differentiation. Moreover, Myt1 L was potently involved in promoting remyelination after lysolecithin-induced demyelination in vivo. Ch IP assays showed that Myt1 L bound to the promoter of Olig1 and transcriptionally regulated Olig1 expression. Taken together, our findings demonstrate that Myt1 L is an essential regulator of OPC differentiation, thereby supporting Myt1 L as a potential therapeutic target for demyelinating diseases.
基金supported by the National Natural Science Foundation of China (31671117).
文摘Oligodendrocyte (OL) and myelin development are crucial for network integration and are associated with higher brain functions. Accumulating evidence has demonstrated structural and functional impairment of OLs and myelin in serious mental illnesses. However, whether these deficits contribute to the brain dysfunction or pathogenesis of such diseases still lacks direct evidence. In this study, we conditionally deleted Olig2 in oligodendroglial lineage cells (Olig2 cKO) and screened the behavioral changes in adult mice. We found that Olig2 ablation impaired myelin development, which further resulted in severe hypomyelination in the anterior cingulate cortex. Strikingly, Olig2 cKO mice exhibited an anxious phenotype, aberrant responses to stress, and cognitive deficits. Moreover, Olig2 cKO mice showed increased vulnerability to social avoidance under the mild stress of social isolation. Together,these results indicate that developmental deficits in OL and myelin lead to cognitive impairment and increase the risk of phenotypes reminiscent of mental illnesses.
