Features, Fates, and Functions of Oligodendrocyte Precursor Cells.

Oligodendrocyte precursor cells (OPCs) are a central nervous system resident population of glia with a distinct molecular identity and an ever-increasing list of functions. OPCs generate oligodendrocytes throughout development and across the life span in most regions of the brain and spinal cord. This process involves a complex coordination of molecular checkpoints and biophysical cues from the environment that initiate the differentiation and integration of new oligodendrocytes that synthesize myelin sheaths on axons. Outside of their progenitor role, OPCs have been proposed to play other functions including the modulation of axonal and synaptic development and the participation in bidirectional signaling with neurons and other glia. Here, we review OPC identity and known functions and discuss recent findings implying other roles for these glial cells in brain physiology and pathology.

Cleavage of VAMP2/3 Affects Oligodendrocyte Lineage Development in the Developing Mouse Spinal Cord.

In the developing and adult CNS, new oligodendrocytes (OLs) are generated from a population of cells known as oligodendrocyte precursor cells (OPCs). As they begin to differentiate, OPCs undergo a series of highly regulated changes to morphology, gene expression, and membrane organization. This stage represents a critical bottleneck in oligodendrogliogenesis, and the regulatory program that guides it is still not fully understood. Here, we show that in vivo toxin-mediated cleavage of the vesicle associated SNARE proteins VAMP2/3 in the OL lineage of both male and female mice impairs the ability of early OLs to mature into functional, myelinating OLs. In the developing mouse spinal cord, many VAMP2/3-cleaved OLs appeared to stall in the premyelinating, early OL stage, resulting in an overall loss of both myelin density and OL number. The Src kinase Fyn, a key regulator of oligodendrogliogenesis and myelination, is highly expressed among premyelinating OLs, but its expression decreases as OLs mature. We found that OLs with cleaved VAMP2/3 in the spinal cord white matter showed significantly higher expression of Fyn compared with neighboring control cells, potentially because of an extended premyelinating stage. Overall, our results show that functional VAMP2/3 in OL lineage cells is essential for proper myelin formation and plays a major role in controlling the maturation and terminal differentiation of premyelinating OLs.SIGNIFICANCE STATEMENT The production of mature oligodendrocytes (OLs) is essential for CNS myelination during development, myelin remodeling in adulthood, and remyelination following injury or in demyelinating disease. Before myelin sheath formation, newly formed OLs undergo a series of highly regulated changes during a stage of their development known as the premyelinating, or early OL stage. This stage acts as a critical checkpoint in OL development, and much is still unknown about the dynamic regulatory processes involved. In this study, we show that VAMP2/3, SNARE proteins involved in vesicular trafficking and secretion play an essential role in regulating premyelinating OL development and are required for healthy myelination in the developing mouse spinal cord.

A new era for myelin research in Neurofibromatosis type 1.

Evidence for myelin regulating higher-order brain function and disease is rapidly accumulating; however, defining cellular/molecular mechanisms remains challenging partially due to the dynamic brain physiology involving deep changes during development, aging, and in response to learning and disease. Furthermore, as the etiology of most neurological conditions remains obscure, most research models focus on mimicking symptoms, which limits understanding of their molecular onset and progression. Studying diseases caused by single gene mutations represents an opportunity to understand brain dys/function, including those regulated by myelin. Here, we discuss known and potential repercussions of abnormal central myelin on the neuropathophysiology of Neurofibromatosis Type 1 (NF1). Most patients with this monogenic disease present with neurological symptoms diverse in kind, severity, and onset/decline, including learning disabilities, autism spectrum disorders, attention deficit and hyperactivity disorder, motor coordination issues, and increased risk for depression and dementia. Coincidentally, most NF1 patients show diverse white matter/myelin abnormalities. Although myelin-behavior links were proposed decades ago, no solid data can prove or refute this idea yet. A recent upsurge in myelin biology understanding and research/therapeutic tools provides opportunities to address this debate. As precision medicine moves forward, an integrative understanding of all cell types disrupted in neurological conditions becomes a priority. Hence, this review aims to serve as a bridge between fundamental cellular/molecular myelin biology and clinical research in NF1.

Presentation and integration of multiple signals that modulate oligodendrocyte lineage progression and myelination.

Myelination is critical for fast saltatory conduction of action potentials. Recent studies have revealed that myelin is not a static structure as previously considered but continues to be made and remodeled throughout adulthood in tune with the network requirement. Synthesis of new myelin requires turning on the switch in oligodendrocytes (OL) to initiate the myelination program that includes synthesis and transport of macromolecules needed for myelin production as well as the metabolic and other cellular functions needed to support this process. A significant amount of information is available regarding the individual intrinsic and extrinsic signals that promote OL commitment, expansion, terminal differentiation, and myelination. However, it is less clear how these signals are made available to OL lineage cells when needed, and how multiple signals are integrated to generate the correct amount of myelin that is needed in a given neural network state. Here we review the pleiotropic effects of some of the extracellular signals that affect myelination and discuss the cellular processes used by the source cells that contribute to the variation in the temporal and spatial availability of the signals, and how the recipient OL lineage cells might integrate the multiple signals presented to them in a manner dialed to the strength of the input.

Electronic, vibrational, and rotational analysis of 1,2-benzanthracene by high-resolution spectroscopy referenced to an optical frequency comb.

The electronic and vibrational structures of 1,2-benzanthracene-h12 (aBA-h12) and 1,2-benzanthracene-d12 (aBA-d12) were elucidated by analyzing fluorescence excitation spectra and dispersed fluorescence spectra in a supersonic jet on the basis of DFT calculation. We also observed the high-resolution and high-precision fluorescence excitation spectrum of the S1←S000 0 band, and determined the accurate rotational constants in the zero-vibrational levels of the S0 and S1 states. In this high-resolution measurement, we used a single-mode UV laser whose frequencies were controlled with reference to an optical frequency comb. The inertial defect is negligibly small, the molecule is considered to be planar, and the obtained rotational constants were well reproduced by the equation-of-motion coupled cluster singles and doubles (EOM-CCSD) calculation. Both a-type and b-type transitions are found to be included in the rotationally resolved spectrum, and the a-type contribution is dominant, that is, the transition moment is nearly parallel to the long axis of the aBA molecule. We concluded that the S1 state is mainly composed of the Φ(B) configuration. The observed fluorescence lifetime (106 ns) is considerably longer than that of the Φ(A) system, such as anthracene (18 ns). The transition moment for the lower state of mixed states becomes small, reflecting a near-cancelation of the contributions from the parts of the wavefunction corresponding to the two electronic configurations. The bandwidth of the S2 ← S0 transition is large, and the structure is complicated. It is attributed to vibronic coupling with the high vibrational levels of the S1 state.

Search for Ultralight Dark Matter from Long-Term Frequency Comparisons of Optical and Microwave Atomic Clocks.

We search for ultralight scalar dark matter candidates that induce oscillations of the fine structure constant, the electron and quark masses, and the quantum chromodynamics energy scale with frequency comparison data between a ^{171}Yb optical lattice clock and a ^{133}Cs fountain microwave clock that span 298 days with an uptime of 15.4%. New limits on the couplings of the scalar dark matter to electrons and gluons in the mass range from 10^{-22} to 10^{-20} eV/c^{2} are set, assuming that each of these couplings is the dominant source of the modulation in the frequency ratio. The absolute frequency of the ^{171}Yb clock transition is also determined as 518 295 836 590 863.69(28) Hz, which is one of the important contributions toward a redefinition of the second in the International System of Units.

Olig2 Ablation in Immature Oligodendrocytes Does Not Enhance CNS Myelination and Remyelination.

The oligodendrocyte (OL) lineage transcription factor Olig2 is expressed throughout oligodendroglial development and is essential for oligodendroglial progenitor specification and differentiation. It was previously reported that deletion of Olig2 enhanced the maturation and myelination of immature OLs and accelerated the remyelination process. However, by analyzing multiple Olig2 conditional KO mouse lines (male and female), we conclude that Olig2 has the opposite effect and is required for OL maturation and remyelination. We found that deletion of Olig2 in immature OLs driven by an immature OL-expressing Plp1 promoter resulted in defects in OL maturation and myelination, and did not enhance remyelination after demyelination. Similarly, Olig2 deletion during premyelinating stages in immature OLs using Mobp or Mog promoter-driven Cre lines also did not enhance OL maturation in the CNS. Further, we found that Olig2 was not required for myelin maintenance in mature OLs but was critical for remyelination after lysolecithin-induced demyelinating injury. Analysis of genomic occupancy in immature and mature OLs revealed that Olig2 targets the enhancers of key myelination-related genes for OL maturation from immature OLs. Together, by leveraging multiple immature OL-expressing Cre lines, these studies indicate that Olig2 is essential for differentiation and myelination of immature OLs and myelin repair. Our findings raise fundamental questions about the previously proposed role of Olig2 in opposing OL myelination and highlight the importance of using Cre-dependent reporter(s) for lineage tracing in studying cell state progression.SIGNIFICANCE STATEMENT Identification of the regulators that promote oligodendrocyte (OL) myelination and remyelination is important for promoting myelin repair in devastating demyelinating diseases. Olig2 is expressed throughout OL lineage development. Ablation of Olig2 was reported to induce maturation, myelination, and remyelination from immature OLs. However, lineage-mapping analysis of Olig2-ablated cells was not conducted. Here, by leveraging multiple immature OL-expressing Cre lines, we observed no evidence that Olig2 ablation promotes maturation or remyelination of immature OLs. Instead, we find that Olig2 is required for immature OL maturation, myelination, and myelin repair. These data raise fundamental questions about the proposed inhibitory role of Olig2 against OL maturation and remyelination. Our findings highlight the importance of validating genetic manipulation with cell lineage tracing in studying myelination.

Dual-comb cavity ring-down spectroscopy.

Cavity ring-down spectroscopy is a ubiquitous optical method used to study light-matter interactions with high resolution, sensitivity and accuracy. However, it has never been performed with the multiplexing advantages of direct frequency comb spectroscopy without significantly compromising spectral resolution. We present dual-comb cavity ring-down spectroscopy (DC-CRDS) based on the parallel heterodyne detection of ring-down signals with a local oscillator comb to yield absorption and dispersion spectra. These spectra are obtained from widths and positions of cavity modes. We present two approaches which leverage the dynamic cavity response to coherently or randomly driven changes in the amplitude or frequency of the probe field. Both techniques yield accurate spectra of methane-an important greenhouse gas and breath biomarker. When combined with broadband frequency combs, the high sensitivity, spectral resolution and accuracy of our DC-CRDS technique shows promise for applications like studies of the structure and dynamics of large molecules, multispecies trace gas detection and isotopic composition.

Shaping of Regional Differences in Oligodendrocyte Dynamics by Regional Heterogeneity of the Pericellular Microenvironment.

Oligodendrocyte precursor cells (OPCs) are glial cells that differentiate into mature oligodendrocytes (OLs) to generate new myelin sheaths. While OPCs are distributed uniformly throughout the gray and white matter in the developing and adult brain, those in white matter proliferate and differentiate into oligodendrocytes at a greater rate than those in gray matter. There is currently lack of evidence to suggest that OPCs comprise genetically and transcriptionally distinct subtypes. Rather, the emerging view is that they exist in different cell and functional states, depending on their location and age. Contrary to the normal brain, demyelinated lesions in the gray matter of multiple sclerosis brains contain more OPCs and OLs and are remyelinated more robustly than those in white matter. The differences in the dynamic behavior of OL lineage cells are likely to be influenced by their microenvironment. There are regional differences in astrocytes, microglia, the vasculature, and the composition of the extracellular matrix (ECM). We will discuss how the regional differences in these elements surrounding OPCs might shape their phenotypic variability in normal and demyelinated states.

The Impact of Fixation on the Detection of Oligodendrocyte Precursor Cell Morphology and Vascular Associations.

Oligodendrocyte precursor cells (OPCs) display numerous protrusions that extend into the surrounding parenchyma in the brain. Depending on the preparation of the tissue analyzed, these protrusions are more or less visible. We applied six different fixation methods and compared the effect of prolonged and stronger fixation on fluorescence intensity of platelet-derived growth factor receptor alpha, a surface marker of OPCs. Importantly, the fluorescence signal is mostly lost on protrusions as compared to the cell body, which has to be considered for specific analyses. Additionally, we show numerous contacts established between OPCs and the brain vasculature, which will contribute to the understanding of the interactions between these two elements.

Microglial neuropilin-1 promotes oligodendrocyte expansion during development and remyelination by trans-activating platelet-derived growth factor receptor.

Nerve-glia (NG2) glia or oligodendrocyte precursor cells (OPCs) are distributed throughout the gray and white matter and generate myelinating cells. OPCs in white matter proliferate more than those in gray matter in response to platelet-derived growth factor AA (PDGF AA), despite similar levels of its alpha receptor (PDGFRα) on their surface. Here we show that the type 1 integral membrane protein neuropilin-1 (Nrp1) is expressed not on OPCs but on amoeboid and activated microglia in white but not gray matter in an age- and activity-dependent manner. Microglia-specific deletion of Nrp1 compromised developmental OPC proliferation in white matter as well as OPC expansion and subsequent myelin repair after acute demyelination. Exogenous Nrp1 increased PDGF AA-induced OPC proliferation and PDGFRα phosphorylation on dissociated OPCs, most prominently in the presence of suboptimum concentrations of PDGF AA. These findings uncover a mechanism of regulating oligodendrocyte lineage cell density that involves trans-activation of PDGFRα on OPCs via Nrp1 expressed by adjacent microglia.

Many roles for oligodendrocyte precursor cells in physiology and pathology.

Oligodendrocyte precursor cells (OPCs) are a fourth resident glial cell population in the mammalian central nervous system. They are evenly distributed throughout the gray and white matter and continue to proliferate and generate new oligodendrocytes (OLs) throughout life. They were understudied until a few decades ago when immunolabeling for NG2 and platelet-derived growth factor receptor alpha revealed cells that are distinct from mature OLs, astrocytes, neurons, and microglia. In this review, we provide a summary of the known properties of OPCs with some historical background, followed by highlights from recent studies that suggest new roles for OPCs in certain pathological conditions.

Life-long oligodendrocyte development and plasticity.

Oligodendrocyte precursor cells (OPCs) originate in localized germinal zones in the embryonic neural tube, then migrate and proliferate to populate the entire central nervous system, both white and gray matter. They divide and generate myelinating oligodendrocytes (OLs) throughout postnatal and adult life. OPCs express NG2 and platelet-derived growth factor receptor alpha subunit (PDGFRα), two functionally important cell surface proteins, which are also widely used as markers for OPCs. The proliferation of OPCs, their terminal differentiation into OLs, survival of new OLs, and myelin synthesis are orchestrated by signals in the local microenvironment. We discuss advances in our mechanistic understanding of paracrine effects, including those mediated through PDGFRα and neuronal activity-dependent signals such as those mediated through AMPA receptors in OL survival and myelination. Finally, we review recent studies supporting the role of new OL production and "adaptive myelination" in specific behaviours and cognitive processes contributing to learning and long-term memory formation. Our article is not intended to be comprehensive but reflects the authors' past and present interests.

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.

Novel guanidine compounds inhibit platelet-derived growth factor receptor alpha transcription and oligodendrocyte precursor cell proliferation.

Oligodendrocyte precursor cells (OPCs), also known as NG2 cells or polydendrocytes, are distributed widely throughout the developing and mature central nervous system. They remain proliferative throughout life and are an important source of myelinating cells in normal and demyelinating brain as well as a source of glioma, the most common type of primary brain tumor with a poor prognosis. OPC proliferation is dependent on signaling mediated by platelet-derived growth factor (PDGF) AA binding to its alpha receptor (PDGFRα). Here, we describe a group of structurally related compounds characterized by the presence of a basic guanidine group appended to an aromatic core that is effective in specifically repressing the transcription of Pdgfra but not the related beta receptor (Pdgfrb) in OPCs. These compounds specifically and dramatically reduced proliferation of OPCs but not that of astrocytes and did not affect signal transduction by PDGFRα. These findings suggest that the compounds could be further developed for potential use in combinatorial treatment strategies for neoplasms with dysregulated PDGFRα function.

Phase-stabilized all-fiber-based mode-filtering technique for generating a gigahertz frequency comb.

An all-fiber-based mode-filtering technique is developed for generating a gigahertz-repetition-rate fiber-based frequency comb with a multiplication factor of 21. A high side-mode suppression ratio of approximately 65 dB is achieved by introducing a thermally diffused expanded core fiber between the dispersion compensating fiber and single-mode fiber to reduce splice loss. The fiber cavity length is also stabilized such that the resonance frequency is locked to the comb mode by applying the Pound-Drever-Hall stabilization technique. The proposed stabilized all-fiber-based mode-filtering technique is expected to be an attractive choice for a variety of applications that require a high-repetition-rate frequency comb.

Ultrahigh finesse cavity-enhanced spectroscopy for accurate tests of quantum electrodynamics for molecules.

We report the most accurate, to the best of our knowledge, measurement of the position of the weak quadrupole S(2) 2-0 line in $ {{\rm D}_2} $D2. The spectra were collected with a frequency-stabilized cavity ringdown spectrometer (FS-CRDS) with an ultrahigh finesse optical cavity ($ {\cal F} = 637 000 $F=637000) and operating in the frequency-agile, rapid scanning spectroscopy (FARS) mode. Despite working in the Doppler-limited regime, we reached 40 kHz of statistical uncertainty and 161 kHz of absolute accuracy, achieving the highest accuracy for homonuclear isotopologues of molecular hydrogen. The accuracy of our measurement corresponds to the fifth significant digit of the leading term in quantum electrodynamics (QED) correction. We observe $ 2.3\sigma $2.3σ discrepancy with the recent theoretical value.

The effects of developmental and current niches on oligodendrocyte precursor dynamics and fate.

Oligodendrocyte precursor cells (OPCs), whose primary function is to generate myelinating oligodendrocytes, are distributed widely throughout the developing and mature central nervous system. They originate from several defined subdomains in the embryonic germinal zones at different developmental stages and in the adult. While many phenotypic differences have been observed among OPCs in different anatomical regions and among those arising from different germinal zones, we know relatively little about the molecular and cellular mechanisms by which the historical and current niches shape the behavior of oligodendrocyte lineage cells. This minireview will discuss how the behavior of oligodendrocyte lineage cells is influenced by the developmental niches from which subpopulations of OPCs emerge, by the current niches surrounding OPCs in different regions, and in pathological states that cause deviations from the normal density of oligodendrocyte lineage cells and myelin.

Electronic and vibrational structure in the S0 and S1 states of corannulene.

Corannulene is a nonplanar aromatic hydrocarbon also known as a buckybowl. Its electronic and vibrational structure has been investigated by analyzing its fluorescence excitation spectrum and dispersed fluorescence spectrum in a supersonic jet. Its spectral features are in keeping with the expectation, confirmed by some previous results, that it has fivefold or C5v symmetry. The observed prominent vibronic bands in the S1 ← S0 transition have been assigned to e1 and e2 bands on the basis of theoretical calculations so that the S1 state was assigned to 1E2. The symmetry adapted cluster configuration interaction calculation supports this assignment of the S1 electronic state, although the time-dependent density functional theory calculation suggests that the S1 state is 1A2. It has also been shown that the normal coordinates for strong vibronic bands mainly include out-of-plane vibrational motion. The rotational envelopes are well explained by taking account of the Coriolis interaction between the degenerate vibrational and rotational levels. The mechanism of bowl-to-bowl inversion is also discussed with the results of theoretical calculations regarding the barrier to inversion and metastable conformation.