Myelin is a multilayer lipid membrane structure that wraps and insulates axons, allowing for the efficient propagation of action potentials. During developmental myelination of the central nervous ...system (CNS), oligodendrocyte progenitor cells (OPCs) proliferate and migrate to their final destination, where they terminally differentiate into mature oligodendrocytes and myelinate axons. Lineage progression and terminal differentiation of oligodendrocyte lineage cells are under tight transcriptional and post-transcriptional control. The characterization of several recently identified regulatory factors that govern these processes, which are the focus of this review, has greatly increased our understanding of oligodendrocyte development and function. These insights are critical to facilitate efforts to enhance OPC differentiation in neurological disorders that disrupt CNS myelin.
The development of oligodendrocyte lineage cells is regulated by tight transcriptional, post-transcriptional, translational, and post-translational control.
The transcription factor SRY-box 10 (SOX10) is a major facilitator of the transcriptional control of oligodendrocyte lineage cell differentiation.
miRNAs are major determinants in the terminal differentiation of oligodendrocytes.
Eukaryotic translation initiation factors have a role in the translational control of oligodendrocyte development.
Post-translational modification of transcription factors has a fundamental role in the transcriptional control of oligodendrocyte development.
Real-world bioelectronics applications, including drug delivery systems, biosensing and electrical modulation of tissues and organs, largely require biointerfaces at the macroscopic level. However, ...traditional macroscale bioelectronic electrodes usually exhibit invasive or power-inefficient architectures, inability to form uniform and subcellular interfaces, or faradaic reactions at electrode surfaces. Here, we develop a micelle-enabled self-assembly approach for a binder-free and carbon-based monolithic device, aimed at large-scale bioelectronic interfaces. The device incorporates a multi-scale porous material architecture, an interdigitated microelectrode layout and a supercapacitor-like performance. In cell training processes, we use the device to modulate the contraction rate of primary cardiomyocytes at the subcellular level to target frequency in vitro. We also achieve capacitive control of the electrophysiology in isolated hearts, retinal tissues and sciatic nerves, as well as bioelectronic cardiac sensing. Our results support the exploration of device platforms already used in energy research to identify new opportunities in bioelectronics.
To become and remain functional, individual neuron types must select during development and maintain throughout life their distinct terminal identity features, such as expression of specific ...neurotransmitter receptors, ion channels and neuropeptides. Here, we report a molecular mechanism that enables cholinergic motor neurons (MNs) in the
ventral nerve cord to select and maintain their unique terminal identity. This mechanism relies on the dual function of the conserved terminal selector UNC-3 (Collier/Ebf). UNC-3 synergizes with LIN-39 (Scr/Dfd/Hox4-5) to directly co-activate multiple terminal identity traits specific to cholinergic MNs, but also antagonizes LIN-39's ability to activate terminal features of alternative neuronal identities. Loss of
causes a switch in the transcriptional targets of LIN-39, thereby alternative, not cholinergic MN-specific, terminal features become activated and locomotion defects occur. The strategy of a terminal selector preventing a transcriptional switch may constitute a general principle for safeguarding neuronal identity throughout life.
Zinc finger protein ZFP24, formerly known as ZFP191, is essential for oligodendrocyte maturation and CNS myelination. Nevertheless, the mechanism by which ZFP24 controls these processes is unknown. ...We demonstrate that ZFP24 binds to a consensus DNA sequence in proximity to genes important for oligodendrocyte differentiation and CNS myelination, and we show that this binding enhances target gene expression. We also demonstrate that ZFP24 DNA binding is controlled by phosphorylation. Phosphorylated ZFP24, which does not bind DNA, is the predominant form in oligodendrocyte progenitor cells. As these cells mature into oligodendrocytes, the non-phosphorylated, DNA-binding form accumulates. Interestingly, ZFP24 displays overlapping genomic binding sites with the transcription factors MYRF, SOX10, and OLIG2, which are known to control oligodendrocyte differentiation. Our findings provide a mechanism by which dephosphorylation of ZFP24 mediates its binding to regulatory regions of genes important for oligodendrocyte maturation, controls their expression, and thereby regulates oligodendrocyte differentiation and CNS myelination.
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•ZFP24 binds to the regulatory regions of genes important for CNS myelination•The DNA-binding capability of ZFP24 is controlled by phosphorylation•The phosphorylation state of ZFP24 changes along the oligodendrocyte lineage•ZFP24 displays overlapping genomic binding sites with MYRF, SOX10, and OLIG2
Elbaz et al. describe a mechanism by which dephosphorylation of the zinc finger protein ZFP24 mediates its binding to the regulatory regions of genes important for oligodendrocyte maturation, controls their expression, and thereby regulates oligodendrocyte differentiation and CNS myelination.
The molecular mechanisms that govern the maturation of oligodendrocyte lineage cells remain unclear. Emerging studies have shown that N6-methyladenosine (m6A), the most common internal RNA ...modification of mammalian mRNA, plays a critical role in various developmental processes. Here, we demonstrate that oligodendrocyte lineage progression is accompanied by dynamic changes in m6A modification on numerous transcripts. In vivo conditional inactivation of an essential m6A writer component, METTL14, results in decreased oligodendrocyte numbers and CNS hypomyelination, although oligodendrocyte precursor cell (OPC) numbers are normal. In vitro Mettl14 ablation disrupts postmitotic oligodendrocyte maturation and has distinct effects on OPC and oligodendrocyte transcriptomes. Moreover, the loss of Mettl14 in oligodendrocyte lineage cells causes aberrant splicing of myriad RNA transcripts, including those that encode the essential paranodal component neurofascin 155 (NF155). Together, our findings indicate that dynamic RNA methylation plays an important regulatory role in oligodendrocyte development and CNS myelination.
•Oligodendrocyte maturation is accompanied by modifications in m6A mRNA methylation•m6A mRNA methylation is required for oligodendrocyte maturation and CNS myelination•m6A mRNA methylation regulates the transcriptomes of oligodendrocyte lineage cells•Proper neurofascin mRNA splicing in oligodendrocytes requires m6A methylation
Xu et al. show that oligodendrocyte development is associated with dynamic changes in posttranscriptional mRNA methylation. Moreover, they demonstrate that the m6A epigenetic RNA mark has considerable impact on the myelinating cell’s transcriptome and is essential for normal CNS myelination.
The transcriptional program that controls oligodendrocyte maturation and central nervous system (CNS) myelination has not been fully characterized. In this study, we use high-throughput RNA ...sequencing to analyze how the loss of a key transcription factor, zinc finger protein 191 (ZFP191), results in oligodendrocyte development abnormalities and CNS hypomyelination. Using a previously described mutant mouse that is deficient in ZFP191 protein expression (Zfp191
null
), we demonstrate that key transcripts are reduced in the whole brain as well as within oligodendrocyte lineage cells cultured in vitro. To determine whether the loss of myelin seen in Zfp191
null
mice contributes indirectly to these perturbations, we also examined the transcriptome of a well-characterized mouse model of hypomyelination, in which the myelin structural protein myelin basic protein (MBP) is deficient. Interestingly, Mbp
shi
(shiverer) mice had far fewer transcripts perturbed with the loss of myelin alone. This study demonstrates that the loss of ZFP191 disrupts expression of genes involved in oligodendrocyte maturation and myelination, largely independent from the loss of myelin. Nevertheless, hypomyelination in both mouse mutants results in the perturbation of lipid synthesis pathways, suggesting that oligodendrocytes have a feedback system that allows them to regulate myelin lipid synthesis depending on their myelinating state. The data presented are of potential clinical relevance as the human orthologs of the Zfp191 and MBP genes reside on a region of Chromosome 18 that is deleted in childhood leukodystrophies.
ABSTRACT
Zn hyperaccumulator plants sequester Zn into their shoot vacuoles. To date, the only transporters implicated in Zn sequestration into the vacuoles of hyperaccumulator plants are cation ...diffusion facilitators (CDFs). We investigated the expression in Arabidopsis halleri of a homolog of AtMHX, an A. thaliana tonoplast transporter that exchanges protons with Mg, Zn and Fe ions. A. halleri has a single copy of a homologous gene, encoding a protein that shares 98% sequence identity with AtMHX. Western blot analysis with vacuolar‐enriched membrane fractions suggests localization of AhMHX in the tonoplast. The levels of MHX proteins are much higher in leaves of A. halleri than in leaves of the non‐accumulator plant A. thaliana. At the same time, the levels of MHX transcripts are similar in leaves of the two species. This suggests that the difference in MHX levels is regulated at the post‐transcriptional level. In vitro translation studies indicated that the difference between AhMHX and AtMHX expression is not likely to result from the variations in the sequence of their 5′ untranslated regions (5′UTRs). The high expression of AhMHX in A. halleri leaves is constitutive and not significantly affected by the metal status of the plants. In both species, MHX transcript levels are higher in leaves than in roots, but the difference is higher in A. halleri. Metal sequestration into root vacuoles was suggested to inhibit hyperaccumulation in the shoot. Our data implicate AhMHX as a candidate gene in metal accumulation or tolerance in A. halleri.
The Na + -Ca 2+ exchanger (NCX) is a major Ca 2+ -regulating protein encoded by three genes: NCX1 , NCX2 , and NCX3. They share a sequence homology of approximately 65%. NCX1 protein is expressed ...ubiquitously, and NCX2 and NCX3 are expressed
almost exclusively in the brain. We have shown previously ( Kimchi-Sarfaty et al., 2002 ) that treatment of NCX1 -transfected human embryonic kidney (HEK) 293 cells with the immunosuppressive cyclosporin A (CsA) and its nonimmunosuppressive
analog PSC833 (valspodar) results in down-regulation of surface expression and transport activity of the protein without a
decrease in expression of cell NCX1 protein. In this study, we show that cyclosporin A and PSC833 treatment of NCX2 - and NCX3 -transfected HEK 293 cells also resulted in dose-dependent down-regulation of surface expression and transport activity of
the two brain NCX proteins; however, whereas CsA had no effect on total cell NCX protein expression, PSC833 reduced mRNA and
cell protein expression of NCX2 and NCX3. Moreover, tacrolimus (FK506), which had no effect on NCX1 protein expression, down-regulated
NCX2 and NCX3 surface expression and transport activity without any significant effect on cell protein expression. Sirolimus
(rapamycin) had no effect on NCX2 and NCX3 protein expression, yet it reduced NCX2 and NCX3 transport activity. Because all
of the experimental conditions in our studies were identical, presumably the different drug response is related to structural
differences between NCX isoforms. Clinical studies suggested that immunosuppressive regimes of patients who have received
transplants resulted in complications related to Ca 2+ . Expression of NCX genes is tissue-specific. Hence, our results can potentially provide a tool for choosing the immunosuppressive
protocol to be used.
Oligodendrocytes are the primary producers of many extracellular matrix (ECM)-related proteins found in the CNS. Therefore, oligodendrocytes play a critical role in the determination of brain ...stiffness, node of Ranvier formation, perinodal ECM deposition, and perineuronal net formation, all of which depend on the ECM. Nevertheless, the transcription factors that control ECM-related gene expression in oligodendrocytes remain unknown. Here, we found that the transcription factor Osterix (also known as Sp7) binds in proximity to genes important for CNS ECM and node of Ranvier formation and mediates their expression. Oligodendrocyte-specific ablation of Sp7 changes ECM composition and brain stiffness and results in aberrant node of Ranvier formation. Sp7 is known to control osteoblast maturation and bone formation. Our comparative analyses suggest that Sp7 plays a conserved biological role in oligodendrocytes and in bone-forming cells, where it mediates brain and bone tissue stiffness by controlling expression of ECM components.
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