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1.
Cell ; 138(1): 172-85, 2009 Jul 10.
Article in English | MEDLINE | ID: mdl-19596243

ABSTRACT

The transcriptional control of CNS myelin gene expression is poorly understood. Here we identify gene model 98, which we have named myelin gene regulatory factor (MRF), as a transcriptional regulator required for CNS myelination. Within the CNS, MRF is specifically expressed by postmitotic oligodendrocytes. MRF is a nuclear protein containing an evolutionarily conserved DNA binding domain homologous to a yeast transcription factor. Knockdown of MRF in oligodendrocytes by RNA interference prevents expression of most CNS myelin genes; conversely, overexpression of MRF within cultured oligodendrocyte progenitors or the chick spinal cord promotes expression of myelin genes. In mice lacking MRF within the oligodendrocyte lineage, premyelinating oligodendrocytes are generated but display severe deficits in myelin gene expression and fail to myelinate. These mice display severe neurological abnormalities and die because of seizures during the third postnatal week. These findings establish MRF as a critical transcriptional regulator essential for oligodendrocyte maturation and CNS myelination.


Subject(s)
Brain/cytology , Gene Expression Regulation , Myelin Sheath/metabolism , Oligodendroglia/metabolism , Transcription Factors/metabolism , Animals , Brain/metabolism , Cell Differentiation , Cells, Cultured , Mice , Neurons/cytology , Neurons/metabolism , Oligodendroglia/cytology
2.
Cell ; 135(4): 596-8, 2008 Nov 14.
Article in English | MEDLINE | ID: mdl-19013270

ABSTRACT

A major challenge to understanding how cells work together in the central nervous system (CNS) is the heterogeneous cellular composition of the brain. In this issue, Heiman et al. (2008) and Doyle et al. (2008) introduce a new strategy (TRAP) that enables the profiling of translated mRNAs in specific CNS cell populations without the need for purifying cells to homogeneity.


Subject(s)
Central Nervous System/metabolism , Animals , Brain/metabolism , Caenorhabditis elegans , Databases, Genetic , Gene Expression Regulation , Genetic Techniques , Humans , Mice , Mice, Transgenic , Models, Biological , Protein Biosynthesis , RNA, Messenger/metabolism
3.
PLoS Genet ; 15(5): e1008130, 2019 05.
Article in English | MEDLINE | ID: mdl-31048900

ABSTRACT

Nanophthalmos is a rare, potentially devastating eye condition characterized by small eyes with relatively normal anatomy, a high hyperopic refractive error, and frequent association with angle closure glaucoma and vision loss. The condition constitutes the extreme of hyperopia or farsightedness, a common refractive error that is associated with strabismus and amblyopia in children. NNO1 was the first mapped nanophthalmos locus. We used combined pooled exome sequencing and strong linkage data in the large family used to map this locus to identify a canonical splice site alteration upstream of the last exon of the gene encoding myelin regulatory factor (MYRF c.3376-1G>A), a membrane bound transcription factor that undergoes autoproteolytic cleavage for nuclear localization. This variant produced a stable RNA transcript, leading to a frameshift mutation p.Gly1126Valfs*31 in the C-terminus of the protein. In addition, we identified an early truncating MYRF frameshift mutation, c.769dupC (p.S264QfsX74), in a patient with extreme axial hyperopia and syndromic features. Myrf conditional knockout mice (CKO) developed depigmentation of the retinal pigment epithelium (RPE) and retinal degeneration supporting a role of this gene in retinal and RPE development. Furthermore, we demonstrated the reduced expression of Tmem98, another known nanophthalmos gene, in Myrf CKO mice, and the physical interaction of MYRF with TMEM98. Our study establishes MYRF as a nanophthalmos gene and uncovers a new pathway for eye growth and development.


Subject(s)
Glaucoma, Angle-Closure/genetics , Hyperopia/genetics , Membrane Proteins/genetics , Microphthalmos/genetics , Retinal Degeneration/genetics , Transcription Factors/genetics , Adult , Animals , Child , Child, Preschool , Exons , Family , Female , Frameshift Mutation/genetics , Genetic Variation/genetics , Glaucoma, Angle-Closure/metabolism , Humans , Hyperopia/metabolism , Male , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Knockout , Microphthalmos/metabolism , Middle Aged , Pedigree , RNA Splice Sites/genetics , Refractive Errors/genetics , Transcription Factors/metabolism
4.
Chem Soc Rev ; 49(15): 5110-5139, 2020 Aug 07.
Article in English | MEDLINE | ID: mdl-32697225

ABSTRACT

In this tutorial review, we will explore recent advances in the construction and application of Förster resonance energy transfer (FRET)-based small-molecule fluorescent probes. The advantages of FRET-based fluorescent probes include: a large Stokes shift, ratiometric sensing and dual/multi-analyte responsive systems. We discuss the underlying energy donor-acceptor dye combinations and emphasise their applications for the detection or imaging of cations, anions, small neutral molecules, biomacromolecules, cellular microenvionments and dual/multi-analyte responsive systems.


Subject(s)
Fluorescence Resonance Energy Transfer/methods , Inorganic Chemicals/analysis , Animals , Biological Transport , Biomedical Enhancement , Biosensing Techniques , Cell Line , Cellular Microenvironment , Humans , Ions/analysis , Membrane Potential, Mitochondrial , Microscopy, Fluorescence , Neoplasms/diagnostic imaging , Optical Imaging , Spectrometry, Fluorescence , Surface Properties
5.
Glia ; 67(11): 2038-2049, 2019 11.
Article in English | MEDLINE | ID: mdl-31038804

ABSTRACT

Myelin is a critical component of the vertebrate nervous system, both increasing the conduction velocity of myelinated axons and allowing for metabolic coupling between the myelinating cells and axons. An increasing number of studies demonstrate that myelination is not simply a developmentally hardwired program, but rather that new myelinating oligodendrocytes can be generated throughout life. The generation of these oligodendrocytes and the formation of myelin are influenced both during development and adulthood by experience and levels of neuronal activity. This led to the concept of adaptive myelination, where ongoing activity-dependent changes to myelin represent a form of neural plasticity, refining neuronal functioning, and circuitry. Although human neuroimaging experiments support the concept of dynamic changes within specific white matter tracts relevant to individual tasks, animal studies have only just begun to probe the extent to which neuronal activity may alter myelination at the level of individual circuits and axons. Uncovering the role of adaptive myelination requires a detailed understanding of the localized interactions that occur between active axons and myelinating cells. In this review, we focus on recent animal studies that have begun to investigate the interactions between active axons and myelinating cells and review the evidence for-and against-the ability of neuronal activity to alter myelination at an axon-specific level.


Subject(s)
Axons/metabolism , Myelin Sheath/metabolism , Neuronal Plasticity/physiology , Oligodendroglia/physiology , Animals , Humans , Neurons/metabolism , White Matter/physiology
6.
Glia ; 67(3): 525-538, 2019 03.
Article in English | MEDLINE | ID: mdl-30506868

ABSTRACT

The identification of factors that regulate myelination provides important insight into the molecular mechanisms that coordinate nervous system development and myelin regeneration after injury. In this study, we investigated the role of amyloid precursor protein (APP) and its paralogue amyloid precursor-like protein 2 (APLP2) in myelination using APP and APLP2 knockout (KO) mice. Given that BACE1 regulates myelination and myelin sheath thickness in both the peripheral and central nervous systems, we sought to determine if APP and APLP2, as alternate BACE1 substrates, also modulate myelination, and therefore provide a better understanding of the events regulating axonal myelination. In the peripheral nervous system, we identified that adult, but not juvenile KO mice, have lower densities of myelinated axons in their sciatic nerves while in the central nervous system, axons within both the optic nerves and corpus callosum of both KO mice were significantly hypomyelinated compared to wild-type (WT) controls. Biochemical analysis demonstrated significant increases in BACE1 and myelin oligodendrocyte glycoprotein and decreased NRG1 and proteolipid protein levels in both KO brain tissue. The acute cuprizone model of demyelination/remyelination revealed that whereas axons in the corpus callosum of WT and APLP2-KO mice underwent similar degrees of demyelination and subsequent remyelination, the myelinated callosal axons in APP-KO mice were less susceptible to cuprizone-induced demyelination and showed a failure in remyelination after cuprizone withdrawal. These data identified APP and APLP2 as modulators of normal myelination and demyelination/remyelination conditions. Deletion of APP and APLP2 identifies novel interplays between the BACE1 substrates in the regulation of myelination.


Subject(s)
Amyloid beta-Protein Precursor/metabolism , Demyelinating Diseases/metabolism , Myelin Sheath/metabolism , Remyelination/physiology , Amyloid Precursor Protein Secretases/genetics , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Protein Precursor/genetics , Animals , Aspartic Acid Endopeptidases/genetics , Aspartic Acid Endopeptidases/metabolism , Axons/metabolism , Corpus Callosum/metabolism , Cuprizone , Demyelinating Diseases/chemically induced , Disease Models, Animal , Male , Mice , Mice, Knockout , Oligodendroglia/metabolism , Optic Nerve/metabolism
7.
Genes Dev ; 24(3): 301-11, 2010 Feb 01.
Article in English | MEDLINE | ID: mdl-20080941

ABSTRACT

The controlling factors that prompt mature oligodendrocytes to myelinate axons are largely undetermined. In this study, we used a forward genetics approach to identify a mutant mouse strain characterized by the absence of CNS myelin despite the presence of abundant numbers of late-stage, process-extending oligodendrocytes. Through linkage mapping and complementation testing, we identified the mutation as a single nucleotide insertion in the gene encoding zinc finger protein 191 (Zfp191), which is a widely expressed, nuclear-localized protein that belongs to a family whose members contain both DNA-binding zinc finger domains and protein-protein-interacting SCAN domains. Zfp191 mutants express an array of myelin-related genes at significantly reduced levels, and our in vitro and in vivo data indicate that mutant ZFP191 acts in a cell-autonomous fashion to disrupt oligodendrocyte function. Therefore, this study demonstrates that ZFP191 is required for the myelinating function of differentiated oligodendrocytes.


Subject(s)
Carrier Proteins/genetics , Carrier Proteins/metabolism , Myelin Sheath/metabolism , Oligodendroglia/metabolism , Alleles , Animals , Cell Differentiation , Cell Line , Cell Proliferation , Cells, Cultured , Central Nervous System/embryology , Embryo, Mammalian/metabolism , Mice , Mice, Transgenic , Mutation
8.
Acta Neuropathol ; 134(3): 403-422, 2017 Sep.
Article in English | MEDLINE | ID: mdl-28631093

ABSTRACT

Remyelination is limited in the majority of multiple sclerosis (MS) lesions despite the presence of oligodendrocyte precursor cells (OPCs) in most lesions. This observation has led to the view that a failure of OPCs to fully differentiate underlies remyelination failure. OPC differentiation requires intricate transcriptional regulation, which may be disrupted in chronic MS lesions. The expression of few transcription factors has been differentially compared between remyelinating lesions and lesions refractory to remyelination. In particular, the oligodendrocyte transcription factor myelin regulatory factor (MYRF) is essential for myelination during development, but its role during remyelination and expression in MS lesions is unknown. To understand the role of MYRF during remyelination, we genetically fate mapped OPCs following lysolecithin-induced demyelination of the corpus callosum in mice and determined that MYRF is expressed in new oligodendrocytes. OPC-specific Myrf deletion did not alter recruitment or proliferation of these cells after demyelination, but decreased the density of new glutathione S-transferase π positive oligodendrocytes. Subsequent remyelination in both the spinal cord and corpus callosum is highly impaired following Myrf deletion from OPCs. Individual OPC-derived oligodendrocytes, produced in response to demyelination, showed little capacity to express myelin proteins following Myrf deletion. Collectively, these data demonstrate a crucial role of MYRF in the transition of oligodendrocytes from a premyelinating to a myelinating phenotype during remyelination. In the human brain, we find that MYRF is expressed in NogoA and CNP-positive oligodendrocytes. In MS, there was both a lower density and proportion of oligodendrocyte lineage cells and NogoA+ oligodendrocytes expressing MYRF in chronically demyelinated lesions compared to remyelinated shadow plaques. The relative scarcity of oligodendrocyte lineage cells expressing MYRF in demyelinated MS lesions demonstrates, for the first time, that chronic lesions lack oligodendrocytes that express this necessary transcription factor for remyelination and supports the notion that a failure to fully differentiate underlies remyelination failure.


Subject(s)
Corpus Callosum/metabolism , Multiple Sclerosis/metabolism , Oligodendroglia/metabolism , Remyelination/physiology , Transcription Factors/metabolism , 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase/metabolism , Animals , Corpus Callosum/pathology , Humans , Mice , Mice, Knockout , Multiple Sclerosis/pathology , Nogo Proteins/metabolism , Oligodendroglia/pathology , Spinal Cord/metabolism , Spinal Cord/pathology , Transcription Factors/genetics
9.
PLoS Biol ; 11(8): e1001625, 2013.
Article in English | MEDLINE | ID: mdl-23966833

ABSTRACT

The myelination of axons is a crucial step during vertebrate central nervous system (CNS) development, allowing for rapid and energy efficient saltatory conduction of nerve impulses. Accordingly, the differentiation of oligodendrocytes, the myelinating cells of the CNS, and their expression of myelin genes are under tight transcriptional control. We previously identified a putative transcription factor, Myelin Regulatory Factor (Myrf), as being vital for CNS myelination. Myrf is required for the generation of CNS myelination during development and also for its maintenance in the adult. It has been controversial, however, whether Myrf directly regulates transcription, with reports of a transmembrane domain and lack of nuclear localization. Here we show that Myrf is a membrane-associated transcription factor that undergoes an activating proteolytic cleavage to separate its transmembrane domain-containing C-terminal region from a nuclear-targeted N-terminal region. Unexpectedly, this cleavage event occurs via a protein domain related to the autoproteolytic intramolecular chaperone domain of the bacteriophage tail spike proteins, the first time this domain has been found to play a role in eukaryotic proteins. Using ChIP-Seq we show that the N-terminal cleavage product directly binds the enhancer regions of oligodendrocyte-specific and myelin genes. This binding occurs via a defined DNA-binding consensus sequence and strongly promotes the expression of target genes. These findings identify Myrf as a novel example of a membrane-associated transcription factor and provide a direct molecular mechanism for its regulation of oligodendrocyte differentiation and CNS myelination.


Subject(s)
Membrane Proteins/metabolism , Transcription Factors/metabolism , Animals , Cell Line , Cells, Cultured , Chromatin Immunoprecipitation , Gene Expression Regulation/genetics , Gene Expression Regulation/physiology , Humans , Membrane Proteins/genetics , Mice , Mutagenesis, Site-Directed , Myelin Sheath/metabolism , Oligodendroglia/metabolism , Transcription Factors/genetics
10.
Glia ; 63(11): 1897-1914, 2015 Nov.
Article in English | MEDLINE | ID: mdl-25974668

ABSTRACT

Myelin is formed by specialized myelinating glia: oligodendrocytes and Schwann cells in the central and peripheral nervous systems, respectively. While there are distinct developmental aspects and regulatory pathways in these two cell types, myelination in both systems requires the transcriptional activator Sox10. Sox10 interacts with cell type-specific transcription factors at some loci to induce myelin gene expression, but it is largely unknown how Sox10 transcriptional networks globally compare between oligodendrocytes and Schwann cells. We used in vivo ChIP-Seq analysis of spinal cord and peripheral nerve (sciatic nerve) to identify unique and shared Sox10 binding sites and assess their correlation with active enhancers and transcriptional profiles in oligodendrocytes and Schwann cells. Sox10 binding sites overlap with active enhancers and critical cell type-specific regulators of myelination, such as Olig2 and Myrf in oligodendrocytes, and Egr2/Krox20 in Schwann cells. Sox10 sites also associate with genes critical for myelination in both oligodendrocytes and Schwann cells and are found within super-enhancers previously defined in brain. In Schwann cells, Sox10 sites contain binding motifs of putative partners in the Sp/Klf, Tead, and nuclear receptor protein families. Specifically, siRNA analysis of nuclear receptors Nr2f1 and Nr2f2 revealed downregulation of myelin genes Mbp and Ndrg1 in primary Schwann cells. Our analysis highlights different mechanisms that establish cell type-specific genomic occupancy of Sox10, which reflects the unique characteristics of oligodendrocyte and Schwann cell differentiation. GLIA 2015;63:1897-1914.

11.
Article in English | MEDLINE | ID: mdl-38503504

ABSTRACT

Myelination has evolved as a mechanism to ensure fast and efficient propagation of nerve impulses along axons. Within the central nervous system (CNS), myelination is carried out by highly specialized glial cells, oligodendrocytes. The formation of myelin is a prolonged aspect of CNS development that occurs well into adulthood in humans, continuing throughout life in response to injury or as a component of neuroplasticity. The timing of myelination is tightly tied to the generation of oligodendrocytes through the differentiation of their committed progenitors, oligodendrocyte precursor cells (OPCs), which reside throughout the developing and adult CNS. In this article, we summarize our current understanding of some of the signals and pathways that regulate the differentiation of OPCs, and thus the myelination of CNS axons.


Subject(s)
Cell Differentiation , Myelin Sheath , Oligodendroglia , Oligodendroglia/physiology , Oligodendroglia/cytology , Humans , Animals , Myelin Sheath/physiology , Myelin Sheath/metabolism , Signal Transduction , Central Nervous System/physiology , Axons/physiology , Axons/metabolism
12.
Curr Pharm Teach Learn ; 16(7): 102100, 2024 Jul.
Article in English | MEDLINE | ID: mdl-38688823

ABSTRACT

BACKGROUND AND PURPOSE: Research training programs in the community pharmacy sector have not been well established. This study showcases a year-long guided research training program undertaken in hospital and community workplaces by pre-registrant pharmacists, and compares the perceived impact on learners in both sectors. EDUCATIONAL ACTIVITY AND SETTING: A two-year cohort study (2021-2022) of pre-registrant pharmacists enrolled in a research training program requiring them to undertake an individual project at their workplace over one year at either a community or hospital workplace. Outcome measures were pre-registrant perceptions of training impact and type of projects completed. FINDINGS: The results of this study demonstrate that the year-long guided research training program delivered to 403 pre-registrant pharmacists was perceived to be impactful to both community and hospital pre-registrant pharmacists and gave them the confidence to pursue further research and see research skills as an important attribute for the profession. Barriers to research included lack of time for both sectors but workplace support and lack of project ideas were especially noted in the community sector. Research project designs were mainly cross-sectional surveys or retrospective audits. SUMMARY: Programs seeking to adopt a similar model may wish to pay particular attention to supporting community pharmacy learners in providing a pre-selection of project ideas, offering training to workplace supervisors, ensuring enough academic support is given and having more check-in points/deliverables to ensure more feedback opportunities.


Subject(s)
Pharmacy Service, Hospital , Humans , Cohort Studies , Female , Male , Surveys and Questionnaires , Adult , Pharmacy Service, Hospital/methods , Pharmacy Service, Hospital/statistics & numerical data , Education, Pharmacy/methods , Education, Pharmacy/statistics & numerical data , Education, Pharmacy/standards , Cross-Sectional Studies , Students, Pharmacy/statistics & numerical data , Students, Pharmacy/psychology , Middle Aged , Community Pharmacy Services/statistics & numerical data , Community Pharmacy Services/standards , Community Pharmacy Services/trends , Pharmacists/statistics & numerical data , Pharmacists/psychology , Retrospective Studies
13.
Cell Rep Med ; 5(4): 101490, 2024 Apr 16.
Article in English | MEDLINE | ID: mdl-38574736

ABSTRACT

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.


Subject(s)
Multiple Sclerosis , Animals , Humans , Multiple Sclerosis/pathology , Retina/pathology , Neurons/pathology , Models, Animal , Atrophy/pathology
14.
J Neurosci ; 32(36): 12528-42, 2012 Sep 05.
Article in English | MEDLINE | ID: mdl-22956843

ABSTRACT

Although the transcription factors required for the generation of oligodendrocytes and CNS myelination during development have been relatively well established, it is not known whether continued expression of the same factors is required for the maintenance of myelin in the adult. Here, we use an inducible conditional knock-out strategy to investigate whether continued oligodendrocyte expression of the recently identified transcription factor myelin gene regulatory factor (MRF) is required to maintain the integrity of myelin in the adult CNS. Genetic ablation of MRF in mature oligodendrocytes within the adult CNS resulted in a delayed but severe CNS demyelination, with clinical symptoms beginning at 5 weeks and peaking at 8 weeks after ablation of MRF. This demyelination was accompanied by microglial/macrophage infiltration and axonal damage. Transcripts for myelin genes, such as proteolipid protein, MAG, MBP, and myelin oligodendrocyte glycoprotein, were rapidly downregulated after ablation of MRF, indicating an ongoing requirement for MRF in the expression of these genes. Subsequently, a proportion of the recombined oligodendrocytes undergo apoptosis over a period of weeks. Surviving oligodendrocytes gradually lose the expression of mature markers such as CC1 antigen and their association with myelin, without reexpressing oligodendrocyte progenitor markers or reentering the cell cycle. These results demonstrate that ongoing expression of MRF within the adult CNS is critical to maintain mature oligodendrocyte identity and the integrity of CNS myelin.


Subject(s)
Central Nervous System/metabolism , Myelin Sheath/metabolism , Oligodendroglia/metabolism , Transcription Factors/physiology , Age Factors , Animals , Cell Differentiation/genetics , Central Nervous System/cytology , Central Nervous System/pathology , Demyelinating Diseases/metabolism , Demyelinating Diseases/pathology , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Myelin Sheath/genetics , Myelin Sheath/ultrastructure , Oligodendroglia/cytology , Transcription Factors/deficiency , Transcription Factors/genetics
15.
Adv Exp Med Biol ; 786: 129-55, 2013.
Article in English | MEDLINE | ID: mdl-23696355

ABSTRACT

With the discovery two decades ago that the adult brain contains neural stem cells (NSCs) capable of producing new neurons, a great deal of research has been undertaken to manipulate these cells to repair the damaged nervous system. Much progress has been made in understanding what regulates adult neural stem cell specification, proliferation and differentiation but much remains to be determined. Lessons can be learned from understanding how embryonic neural stem cells produce the exquisitely complicated organ that is the adult mammalian nervous system. This review will highlight the role of transcriptional regulation of mammalian neural stem cells during embryonic development and compare these to the adult neural stem cell/neural precursor cell (NPC) niches of the subventricular zone (SVZ) of the lateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus. Normal physiological NSC/NPC regulation will be explored, as well as their regulation and responses following neural injury and disease. Finally, transcriptional regulation of the endogenous NSC/NPCs will be compared and contrasted with embryonic stem/induced pluripotent stem (ES/iPS) cell-derived NSC/NPCs. Recapitulation of the embryonic sequence of transcriptional events in neural stem cell development into specific neuronal or glial lineages improves directed differentiation of ES/iPS cells and may be useful for activation and specification of endogenous adult neural stem cells for therapeutic purposes.


Subject(s)
Dentate Gyrus/metabolism , Gene Expression Regulation, Developmental , Induced Pluripotent Stem Cells/metabolism , Lateral Ventricles/metabolism , Neural Stem Cells/metabolism , Neurons/metabolism , Transcription, Genetic , Animals , Cell Differentiation , Cell Proliferation , Dentate Gyrus/cytology , Dentate Gyrus/growth & development , Epigenesis, Genetic , Humans , Induced Pluripotent Stem Cells/cytology , Lateral Ventricles/cytology , Lateral Ventricles/growth & development , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Neural Stem Cells/cytology , Neurons/cytology , Signal Transduction , Transcription Factors/genetics , Transcription Factors/metabolism
16.
Neuron ; 111(2): 139-141, 2023 01 18.
Article in English | MEDLINE | ID: mdl-36657394

ABSTRACT

Oligodendrocyte precursor cells (OPCs) use the vasculature as a scaffold for their migration. In this issue of Neuron, Su et al. determine that astrocytic ensheathment of the vasculature mediates OPC detachment from blood vessels via the secretion of semaphorins, regulating the timing of oligodendrocyte differentiation.


Subject(s)
Oligodendrocyte Precursor Cells , Oligodendroglia , Oligodendroglia/physiology , Astrocytes/physiology , Neurons , Neurogenesis , Oligodendrocyte Precursor Cells/physiology , Cell Differentiation/physiology
17.
bioRxiv ; 2023 Oct 12.
Article in English | MEDLINE | ID: mdl-37873342

ABSTRACT

Chronic demyelination is theorized to contribute to neurodegeneration and drive progressive disability in demyelinating diseases like multiple sclerosis. Here, we describe two genetic mouse models of inducible demyelination, one distinguished by effective remyelination, and the other by remyelination failure and persistent demyelination. By comparing these two models, we find that remyelination protects neurons from apoptosis, improves conduction, and promotes functional recovery. Chronic demyelination of neurons leads to activation of the mitogen-associated protein kinase (MAPK) stress pathway downstream of dual leucine zipper kinase (DLK), which ultimately induces the phosphorylation of c-Jun in the nucleus. Both pharmacological inhibition and CRISPR/Cas9-mediated disruption of DLK block c-Jun phosphorylation and the apoptosis of demyelinated neurons. These findings provide direct experimental evidence that remyelination is neuroprotective and identify DLK inhibition as a potential therapeutic strategy to protect chronically demyelinated neurons.

18.
Cell Chem Biol ; 29(10): 1467-1469, 2022 10 20.
Article in English | MEDLINE | ID: mdl-36270232

ABSTRACT

In this issue, Häberlein et al. demonstrate a role for GPR17 in regulating zebrafish oligodendrocyte differentiation. Zebrafish expressing a humanized GPR17 respond to modulators, which are inactive against the endogenous zebrafish receptor. These findings highlight the potential for humanized zebrafish as an in vivo platform for targeted remyelination drug screens.


Subject(s)
Oligodendroglia , Zebrafish , Animals , Drug Discovery , Nerve Tissue Proteins
19.
Commun Biol ; 5(1): 511, 2022 05 30.
Article in English | MEDLINE | ID: mdl-35637313

ABSTRACT

Oligodendrocyte progenitor cells (OPCs) express protocadherin 15 (Pcdh15), a member of the cadherin superfamily of transmembrane proteins. Little is known about the function of Pcdh15 in the central nervous system (CNS), however, Pcdh15 expression can predict glioma aggression and promote the separation of embryonic human OPCs immediately following a cell division. Herein, we show that Pcdh15 knockdown significantly increases extracellular signal-related kinase (ERK) phosphorylation and activation to enhance OPC proliferation in vitro. Furthermore, Pcdh15 knockdown elevates Cdc42-Arp2/3 signalling and impairs actin kinetics, reducing the frequency of lamellipodial extrusion and slowing filopodial withdrawal. Pcdh15 knockdown also reduces the number of processes supported by each OPC and new process generation. Our data indicate that Pcdh15 is a critical regulator of OPC proliferation and process motility, behaviours that characterise the function of these cells in the healthy CNS, and provide mechanistic insight into the role that Pcdh15 might play in glioma progression.


Subject(s)
Glioma , Oligodendrocyte Precursor Cells , Cadherin Related Proteins , Cell Proliferation , Glioma/genetics , Glioma/metabolism , Humans , Oligodendroglia , Protocadherins
20.
Cell Chem Biol ; 29(2): 239-248.e4, 2022 02 17.
Article in English | MEDLINE | ID: mdl-34375614

ABSTRACT

Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease-associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. Here, we report that TREM2 is a thyroid hormone-regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone and synthetic thyroid hormone agonists (thyromimetics). Our findings report the endocrine regulation of TREM2 by thyroid hormone, and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small-molecule therapeutic agents.


Subject(s)
Acetates/pharmacology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Membrane Glycoproteins/genetics , Microglia/drug effects , Phenols/pharmacology , Receptors, Immunologic/genetics , Retinoid X Receptors/genetics , Thyroid Hormones/pharmacology , Acetates/chemical synthesis , Animals , Binding Sites , Brain/drug effects , Brain/immunology , Brain/pathology , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Gene Expression Regulation , Humans , Immunity, Innate , Macrophages/drug effects , Macrophages/immunology , Macrophages/pathology , Membrane Glycoproteins/antagonists & inhibitors , Membrane Glycoproteins/immunology , Mice , Mice, Inbred C57BL , Microglia/immunology , Microglia/pathology , Models, Molecular , Phenols/chemical synthesis , Phenoxyacetates/pharmacology , Promoter Regions, Genetic , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/genetics , RNA, Messenger/immunology , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/immunology , Response Elements , Retinoid X Receptors/chemistry , Retinoid X Receptors/metabolism , Signal Transduction
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