共查询到20条相似文献,搜索用时 31 毫秒
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Kentaro Kato Daijiro Konno Martin Berry Fumio Matsuzaki Ann Logan Alicia Hidalgo 《PloS one》2015,10(12)
Central nervous system injury induces a regenerative response in ensheathing glial cells comprising cell proliferation, spontaneous axonal remyelination, and limited functional recovery, but the molecular mechanisms are not fully understood. In Drosophila, this involves the genes prospero and Notch controlling the balance between glial proliferation and differentiation, and manipulating their levels in glia can switch the response to injury from prevention to promotion of repair. In the mouse, Notch1 maintains NG2 oligodendrocyte progenitor cells (OPCs) in a progenitor state, but what factor may enable oligodendrocyte (OL) differentiation and functional remyelination is not understood. Here, we asked whether the mammalian homologue of prospero, Prox1, is involved. Our data show that Prox1 is distributed in NG2+ OPCs and in OLs in primary cultured cells, and in the mouse spinal cord in vivo. siRNA prox1 knockdown in primary OPCs increased cell proliferation, increased NG2+ OPC cell number and decreased CC1+ OL number. Prox1 conditional knockout in the OL cell lineage in mice increased NG2+ OPC cell number, and decreased CC1+ OL number. Lysolecithin-induced demyelination injury caused a reduction in CC1+ OLs in homozygous Prox1-/- conditional knockout mice compared to controls. Remarkably, Prox1-/- conditional knockout mice had smaller lesions than controls. Altogether, these data show that Prox1 is required to inhibit OPC proliferation and for OL differentiation, and could be a relevant component of the regenerative glial response. Therapeutic uses of glia and stem cells to promote regeneration and repair after central nervous system injury would benefit from manipulating Prox1. 相似文献
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Andreia Barateiro Veronique E. Miron Sofia D. Santos João B. Relvas Adelaide Fernandes Charles ffrench-Constant Dora Brites 《Molecular neurobiology》2013,47(2):632-644
High levels of serum unconjugated bilirubin (UCB) in newborns are associated with axonal damage and glial reactivity that may contribute to subsequent neurologic injury and encephalopathy (kernicterus). Impairments in myelination and white matter damage were observed at autopsy in kernicteric infants. We have recently reported that UCB reduces oligodendrocyte progenitor cell (OPC) survival in a pure OPC in vitro proliferative culture. Here, we hypothesized that neonatal hyperbilirubinemia may also impair oligodendrocyte (OL) maturation and myelination. We used an experimental model of hyperbilirubinemia that has been shown to mimic the pathophysiological conditions leading to brain dysfunction by unbound (free) UCB. Using primary cultures of OL, we demonstrated that UCB delays cell differentiation by increasing the OPC number and reducing the number of mature OL. This finding was combined with a downregulation of Olig1 mRNA levels and upregulation of Olig2 mRNA levels. Addition of UCB, prior to or during differentiation, impaired OL morphological maturation, extension of processes and cell diameter. Both conditions reduced active guanosine triphosphate (GTP)-bound Rac1 fraction. In myelinating co-cultures of dorsal root ganglia neurons and OL, UCB treatment prior to the onset of myelination decreased oligodendroglial differentiation and the number of myelinating OL, also observed when UCB was added after the onset of myelination. In both circumstances, UCB decreased the number of myelin internodes per OL, as well as the myelin internode length. Our studies demonstrate that increased concentrations of UCB compromise myelinogenesis, thereby elucidating a potential deleterious consequence of elevated UCB. 相似文献
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《遗传学报》2022,49(2):132-144
Glioma is the most common type of tumor in the central nervous system, accounting for around 80% of all malignant brain tumors. Previous studies showed a significant association between nuclear morphology and the malignant progress of gliomas. By virtue of integrated proteomics and genomics analyses as well as experimental validations, we identify three nuclear lamin genes (LMNA, LMNB1, and LMNB2) that are significantly upregulated in glioma tissues compared with normal brain tissues. We show that elevated expressions of LMNB1, LMNB2, and LMNA in glioma cells are highly associated with the rapid progression of the disease and the knockdown of LMNB1, LMNB2, and LMNA dramatically suppresses glioma progression in both in vitro and in vivo mouse models. Moreover, the repression of glioma cell growth by lamin knockdown is mediated by the pRb-mediated G1-S inhibition. On the contrary, overexpression of lamins in normal human astrocytes dramatically induced nuclear morphological aberrations and accelerated cell growth. Together, our multi-omics-based analysis has revealed a previously unrecognized role of lamin genes in gliomagenesis, providing a strong support for the key link between aberrant tumor nuclear shape and the survival of glioma patients. Based on these findings, lamins are proposed to be potential oncogene targets for therapeutic treatments of brain tumors. 相似文献
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The generation of myelinating cells from multipotential neural stem cells in the CNS requires the initiation of specific gene expression programs in oligodendrocytes (OLs). We reasoned that microRNAs (miRNAs) could play an important role in this process by regulating genes crucial for OL development. Here we identified miR-7a as one of the highly enriched miRNAs in oligodendrocyte precursor cells (OPCs), overexpression of which in either neural progenitor cells (NPCs) or embryonic mouse cortex promoted the generation of OL lineage cells. Blocking the function of miR-7a in differentiating NPCs led to a reduction in OL number and an expansion of neuronal populations simultaneously. We also found that overexpression of this miRNA in purified OPC cultures promoted cell proliferation and inhibited further maturation. In addition, miR-7a might exert the effects just mentioned partially by directly repressing proneuronal differentiation factors including Pax6 and NeuroD4, or proOL genes involved in oligodendrocyte maturation. These results suggest that miRNA pathway is essential in determining cell fate commitment for OLs and thus providing a new strategy for modulating this process in OL loss diseases. 相似文献
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Laura A Murray-Nerger Joshua L Justice Pranav Rekapalli Josiah E Hutton Ileana
M Cristea 《Nucleic acids research》2021,49(4):2044
The integrity and regulation of the nuclear lamina is essential for nuclear organization and chromatin stability, with its dysregulation being linked to laminopathy diseases and cancer. Although numerous posttranslational modifications have been identified on lamins, few have been ascribed a regulatory function. Here, we establish that lamin B1 (LMNB1) acetylation at K134 is a molecular toggle that controls nuclear periphery stability, cell cycle progression, and DNA repair. LMNB1 acetylation prevents lamina disruption during herpesvirus type 1 (HSV-1) infection, thereby inhibiting virus production. We also demonstrate the broad impact of this site on laminar processes in uninfected cells. LMNB1 acetylation negatively regulates canonical nonhomologous end joining by impairing the recruitment of 53BP1 to damaged DNA. This defect causes a delay in DNA damage resolution and a persistent activation of the G1/S checkpoint. Altogether, we reveal LMNB1 acetylation as a mechanism for controlling DNA repair pathway choice and stabilizing the nuclear periphery. 相似文献
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Evgueni Doukhanine Christina Gavino Jeffery D. Haines Guillermina Almazan Stéphane Richard 《Molecular biology of the cell》2010,21(17):3029-3040
The quaking viable (qkv) mice represent an animal model of dysmyelination. The absence of expression of the QKI-6 and QKI-7 cytoplasmic isoforms in oligodendrocytes (OLs) during CNS myelination causes the qkv mouse phenotype. The QKI RNA-binding proteins are known to regulate RNA metabolism of cell cycle proteins and myelin components in OLs; however, little is known of their role in reorganizing the cytoskeleton or process outgrowth during OL maturation and differentiation. Here, we identify the actin-interacting protein (AIP)-1 mRNA as a target of QKI-6 by using two-dimensional differential gel electrophoresis. The AIP-1 mRNA contains a consensus QKI response element within its 3′-untranslated region that, when bound by QKI-6, decreases the half-life of the AIP-1 mRNA. Although the expression of QKI-6 is known to increase during OL differentiation and CNS myelination, we show that this increase is paralleled with a corresponding decrease in AIP-1 expression in rat brains. Furthermore, qkv/qkv mice that lack QKI-6 and QKI-7 within its OLs had an increased level of AIP-1 in OLs. Moreover, primary rat OL precursors harboring an AIP-1 small interfering RNA display defects in OL process outgrowth. Our findings suggest that the QKI RNA-binding proteins regulate OL differentiation by modulating the expression of AIP-1. 相似文献
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Picou F Fauquier T Chatonnet F Flamant F 《Molecular endocrinology (Baltimore, Md.)》2012,26(4):608-618
Thyroid hormone (T(3)) can trigger a massive differentiation of cultured oligodendrocytes precursor cells (OPC) by binding the nuclear T(3) receptor α1 (TRα1). Whether this reflects a physiological function of TRα1 remains uncertain. Using a recently generated mouse model, in which CRE/loxP recombination is used to block its function, we show that TRα1 acts at two levels for the in vivo differentiation of OPC in mouse cerebellum. At the early postnatal stage, it promotes the secretion of several neurotrophic factors by acting in Purkinje neurons and astrocytes, defining an environment suitable for OPC differentiation. At later stages, TRα1 acts in a cell-autonomous manner to ensure the complete arrest of OPC proliferation. These data explain contradictory observations made on various models and outline the importance of T(3) signaling both for synchronizing postnatal neurodevelopment and restraining OPC proliferation in adult brain. 相似文献
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The timing of oligodendrocyte development is regulated by thyroid hormone (TH) in vitro and in vivo, but it is still uncertain which TH receptors mediate this regulation. TH acts through nuclear receptors that are encoded by two genes, TRalpha and TRbeta. Here, we provide direct evidence for the involvement of the TRalpha1 receptor isoform in vivo, by showing that the number of oligodendrocytes in the postnatal day 7 (P7) and P14 optic nerve of TRalpha1-/- mice is decreased compared with normal. We demonstrate that TRalpha1 mediates the normal differentiation-promoting effect of TH on oligodendrocyte precursor cells (OPCs): unlike wild-type OPCs, postnatal TRalpha1-/- OPCs fail to stop dividing and differentiate in response to TH in culture. We also show that overexpression of TRalpha1 accelerates oligodendrocyte differentiation in culture, suggesting that the level of TRalpha1 expression is normally limiting for TH-dependent OPC differentiation. Finally, we provide evidence that the inhibitory isoforms of TRalpha are unlikely to play a part in the timing of OPC differentiation. 相似文献
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Sequencing of the reannotated LMNB2 gene reveals novel mutations in patients with acquired partial lipodystrophy
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Hegele RA Cao H Liu DM Costain GA Charlton-Menys V Rodger NW Durrington PN 《American journal of human genetics》2006,79(2):383-389
The etiology of acquired partial lipodystrophy (APL, also called "Barraquer-Simons syndrome") is unknown. Genomic DNA mutations affecting the nuclear lamina protein lamin A cause inherited partial lipodystrophy but are not found in patients with APL. Because it also encodes a nuclear lamina protein (lamin B2) and its genomic structure was recently reannotated, we sequenced LMNB2 as a candidate gene in nine white patients with APL. In four patients, we found three new rare mutations in LMNB2: intron 1 -6G-->T, exon 5 c.643G-->A (p.R215Q; in two patients), and exon 8 c.1218G-->A (p.A407T). The combined frequency of these mutations was 0.222 in the patients with APL, compared with 0.0018 in a multiethnic control sample of 1,100 subjects (P = 2.1 x 10-7) and 0.0045 in a sample of 330 white controls (P = 1.2 x 10-5). These novel heterozygous mutations are the first reported for LMNB2, are the first reported among patients with APL, and indicate how sequencing of a reannotated candidate gene can reveal new disease-associated mutations. 相似文献
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Expression of a beta 1-related integrin by oligodendroglia in primary culture: evidence for a functional role in myelination
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《The Journal of cell biology》1994,124(6):1039-1046
We have investigated the expression of integrins by rat oligodendroglia grown in primary culture and the functional role of these proteins in myelinogenesis. Immunochemical analysis, using antibodies to a number of alpha and beta integrin subunits, revealed that oligodendrocytes express only one detectable integrin receptor complex (alpha OL beta OL). This complex is immunoprecipitated by a polyclonal anti-human beta 1 integrin subunit antibody. In contrast, astrocytes, the other major glial cell type in brain, express multiple integrins including alpha 1 beta 1, alpha 3 beta 1, and alpha 5 beta 1 complexes that are immunologically and electrophoretically indistinguishable from integrins expressed by rat fibroblasts. The beta subunit of the oligodendrocyte integrin (beta OL) and rat fibroblast beta 1 have different electrophoretic mobilities in SDS-PAGE. However, the two beta subunits appear to be highly related based on immunological cross- reactivity and one-dimensional peptide mapping. After removal of N- linked carbohydrate chains, beta OL and beta 1 comigrated in SDS-PAGE and peptide maps of the two deglycosylated subunits were identical, suggesting differential glycosylation of beta 1 and beta OL accounts entirely for their size differences. The oligodendrocyte alpha subunit, alpha OL, was not immunoprecipitated by antibodies against well characterized alpha chains which are known to associate with beta 1 (alpha 3, alpha 4, and alpha 5). However, an antibody to alpha 8, a more recently identified integrin subunit, did precipitate two integrin subunits with electrophoretic mobilities in SDS-PAGE identical to alpha OL and beta OL. Functional studies indicated that disruption of oligodendrocyte adhesion to a glial-derived matrix by an RGD-containing synthetic peptide resulted in a substantial decrease in the level of mRNAs for several myelin components including myelin basic protein (MBP), proteolipid protein (PLP), and cyclic nucleotide phosphodiesterase (CNP). These results suggest that integrin-mediated adhesion of oligodendrocytes may trigger signal(s) that induce the expression of myelin genes and thus influence oligodendrocyte differentiation. 相似文献
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Genoud S Lappe-Siefke C Goebbels S Radtke F Aguet M Scherer SS Suter U Nave KA Mantei N 《The Journal of cell biology》2002,158(4):709-718
We have selectively inhibited Notch1 signaling in oligodendrocyte precursors (OPCs) using the Cre/loxP system in transgenic mice to investigate the role of Notch1 in oligodendrocyte (OL) development and differentiation. Early development of OPCs appeared normal in the spinal cord. However, at embryonic day 17.5, premature OL differentiation was observed and ectopic immature OLs were present in the gray matter. At birth, OL apoptosis was strongly increased in Notch1 mutant animals. Premature OL differentiation was also observed in the cerebrum, indicating that Notch1 is required for the correct spatial and temporal regulation of OL differentiation in various regions of the central nervous system. These findings establish a widespread function of Notch1 in the late steps of mammalian OPC development in vivo. 相似文献
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Caterina Giacomini Sameehan Mahajani Roberta Ruffilli Roberto Marotta Laura Gasparini 《Molecular biology of the cell》2016,27(1):35-47
Lamin B1, a key component of the nuclear lamina, plays an important role in brain development and function. A duplication of the human lamin B1 (LMNB1) gene has been linked to adult-onset autosomal dominant leukodystrophy, and mouse and human loss-of-function mutations in lamin B1 are susceptibility factors for neural tube defects. In the mouse, experimental ablation of endogenous lamin B1 (Lmnb1) severely impairs embryonic corticogenesis. Here we report that in primary mouse cortical neurons, LMNB1 overexpression reduces axonal outgrowth, whereas deficiency of endogenous Lmnb1 results in aberrant dendritic development. In the absence of Lmnb1, both the length and complexity of dendrites are reduced, and their growth is unresponsive to KCl stimulation. This defective dendritic outgrowth stems from impaired ERK signaling. In Lmnb1-null neurons, ERK is correctly phosphorylated, but phospho-ERK fails to translocate to the nucleus, possibly due to delocalization of nuclear pore complexes (NPCs) at the nuclear envelope. Taken together, these data highlight a previously unrecognized role of lamin B1 in dendrite development of mouse cortical neurons through regulation of nuclear shuttling of specific signaling molecules and NPC distribution. 相似文献
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Packiasamy A. R. Juliet Emma E. Frost Janani Balasubramaniam Marc R. Del Bigio 《Journal of neurochemistry》2009,109(5):1285-1299
The germinal matrix of human brain gives rise to oligodendrocytes and astrocytes after mid-gestation. Hemorrhage in the germinal matrix of premature infants is associated with suppressed cell proliferation. We hypothesize that soluble blood constituents have an adverse effect on the proliferation of cultured rat subventricular zone (SVZ) cells and the proliferation, migration, and differentiation of oligodendrocyte progenitor cells (OPC). Using caspase 3 activation and lactate dehydrogenase release assays, rat plasma, serum, thrombin, and kallikrein killed SVZ cells when grown in the presence (but not absence) of platelet derived growth factor. Plasma and serum killed OPC at 1 : 1 to 1 : 100 dilutions. Using a bromodeoxyuridine incorporation assay OPC proliferation was reduced by plasma, serum, thrombin and plasmin. Blood proteins also suppressed OPC migration in a concentration dependent manner. However, differentiation of OPC into myelin basic protein expressing cells was suppressed only by thrombin. We conclude that soluble blood components, particularly thrombin, have an adverse effect on maturing SVZ cells and OPC derived from newborn rat brain. 相似文献
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《Bioorganic & medicinal chemistry letters》2020,30(16):127299
Inducing oligodendrocyte progenitor cell (OPC) differentiation is a novel therapeutic strategy for the treatment of demyelinating diseases such as multiple sclerosis (MS). In the preceding article, we detailed the discovery of compound 1, a potent inducer of OPC differentiation possessing a characteristic spiroindoline structure. Also, we found that N-methylation and des-carbonyl compound 1 (4) led to a loss in potency. Herein, we describe our investigations of a conformation-based hypothesis for OPC differentiation activity based on the preferred conformation of the spiro core, and further structure–activity relationship (SAR) exploration led to the identification of 6-CF3 derivative 8, which was more potent compared to compound 1. 相似文献
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Myelin in the mammalian central nervous system (CNS) is produced by oligodendrocytes, most of which arise from oligodendrocyte precursor cells (OPCs) during late embryonic and early postnatal development. Both external and internal cues have been implicated in regulating OPC exit from the cell cycle and differentiation into oligodendrocytes. In this study, we demonstrate that differentiation of cultured OPCs into mature oligodendrocytes is associated with lower levels of activity of telomerase, the ribonucleoprotein that synthesizes telomeric DNA at the ends of chromosomes. Differentiation is also associated with lower levels of mRNA encoding the catalytic subunit of telomerase (TERT), whereas no difference is seen in the expression of its telomeric template RNA component (TR). These data suggest a possible role for telomerase during normal growth and differentiation of oligodendrocytes that may be relevant to the mechanism of myelination in the CNS. © 2001 John Wiley & Sons, Inc. J Neurobiol 49: 224–234, 2001 相似文献
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Mohamed A. Al-Griw Rabia O. Alghazeer Nuri Awayn Ghalia Shamlan Areej A. Eskandrani Afnan M. Alnajeebi Nouf A. Babteen Wafa S. Alansari 《Saudi Journal of Biological Sciences》2021,28(1):310-316
Cellular elements of maturing brain are vulnerable to insults, which lead to neurodevelopmental defects. There are no established treatments at present. Here we examined the efficacy of selective adenosine A2A receptor inhibitor SCH58261 to combat brain injury, particularly oligodendrocyte (OL) lineage cells, in young rats. Wistar rats (n = 24, 6.5 days old) were randomly divided into equal groups of four. The sham (SHAM) group received no treatment, the vehicle (VEHICLE) group received 0.1% dimethylsufoxide, the injury (INJ) group was exposed to oxygen-glucose deprivation insult, and the injury+SCH58261 (INJ+SCH58261) group was exposed to the insult and received 1 μM SCH58261. Immunocytochemical experiments revealed that there was a significant reduction in the populations of mature OL (MBP+ OLs) and immature OL precursors (NG2+ OPCs) in the INJ group compared to SHAM group. Furthermore, there was also a significant increase in the percent of apoptotic MBP+ OL and NG2+ OPC populations as evidenced by TUNEL assay. In addition, there was a significant reduction in the proliferation rate among NG2+ OPCs, which was confirmed by BrdU immunostaining. On the other hand, treatment with SCH58261 significantly enhanced survival, evidenced by the reduction in apoptotic indices for both cell types, and it is preserved the NG2+ OPC proliferation. Activation of adenosine A2A receptors may contribute to OL lineage cell loss in association with decreased mitotic behavior of OPCs in neonatal brains upon injury. Future investigations assessing ability of SCH58261 to regenerate myelin will provide insights into its wider clinical relevance. 相似文献