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Huntington’s disease (HD) is a neurodegenerative disorder caused by an expanded polyglutamine tract in the huntingtin (HTT) protein. Mutant HTT (mHTT) toxicity is caused by its aggregation/oligomerization. The striatum is the most vulnerable region, although all brain regions undergo neuronal degeneration in the disease. Here we show that the levels of Bim, a BH3-only protein, are significantly increased in HD human post-mortem and HD mouse striata, correlating with neuronal death. Bim reduction ameliorates mHTT neurotoxicity in HD cells. In the HD mouse model, heterozygous Bim knockout significantly mitigates mHTT accumulation and neuronal death, ameliorating disease-associated phenotypes and lifespan. Therefore, Bim could contribute to the progression of HD.

Oligodendrocytes (OLs) continue to be generated from OL precursors (OPs) in the adult mammalian brain. Adult-born OLs are believed to contribute to neural plasticity, learning and memory through a process of "adaptive myelination," but how adult OL generation and adaptive myelination are regulated remains unclear. Here, we report that the glia-specific G protein-coupled receptor 37-like 1 (GPR37L1) is expressed in subsets of OPs and newly formed immature OLs in adult mouse brain. We found that OP proliferation and differentiation are inhibited in the corpus callosum of adult Gpr37l1 knockout mice, leading to a reduction in the number of adult-born OLs. Our data raise the possibility that GPR37L1 is mechanistically involved in adult OL generation and adaptive myelination, and suggest that GPR37L1 might be a useful functional marker of OPs that are committed to OL differentiation.

Summary The mediobasal hypothalamus (MBH; arcuate nucleus of the hypothalamus [ARH] and median eminence [ME]) is a key nutrient sensing site for the production of the complex homeostatic feedback responses required for the maintenance of energy balance. Here, we show that refeeding after an overnight fast rapidly triggers proliferation and differentiation of oligodendrocyte progenitors, leading to the production of new oligodendrocytes in the ME specifically. During this nutritional paradigm, ME perineuronal nets (PNNs), emerging regulators of ARH metabolic functions, are rapidly remodeled, and this process requires myelin regulatory factor (Myrf) in oligodendrocyte progenitors. In genetically obese ob/ob mice, nutritional regulations of ME oligodendrocyte differentiation and PNN remodeling are blunted, and enzymatic digestion of local PNN increases food intake and weight gain. We conclude that MBH PNNs are required for the maintenance of energy balance in lean mice and are remodeled in the adult ME by the nutritional control of oligodendrocyte differentiation., Graphical abstract, Highlights • The median eminence contains a dense population of newly formed oligodendrocytes • Nutritional signals regulate oligodendrocyte differentiation in the median eminence • Oligodendrocyte plasticity in the median eminence regulates local perineuronal nets, Kohnke et al. find that median eminence oligodendrocyte proliferation and differentiation uniquely respond to nutritional signals, revealing the plasticity of this cell type. They directly implicate adult-born oligodendrocytes in the regulation of local perineuronal nets,and show that these extracellular structures modulate the control of energy balance.

Wnt/β-catenin signaling is a well-established driver of colon cancer; however, a targeted therapeutic agent has not reached clinics yet. In the present study, we report that the natural compound liquidambaric acid (LDA) inhibits oncogenic Wnt/β-catenin signaling in vitro and in vivo through its direct target tumor necrosis factor receptor-associated factor 2 (TRAF2). Mechanistically, TRAF2 positively regulates Wnt signaling by interacting with the N-terminal of β-catenin via its TRAF-C domain; this interaction is disrupted in presence of LDA. Particularly, a TRAF2/β-catenin/TCF4/TNIK complex is present in colon cancer cells, where TRAF2 is indispensable for the complex formation, and TRAF2/β-catenin and β-catenin/TCF4 interactions are disrupted upon LDA treatment. Our findings not only highlight that TRAF2 is an oncogenic regulator of Wnt/β-catenin signaling and colon cancer but also provide a lead compound targeting TRAF2 for cancer therapy.

Given the growing evidence of a link between gut microbiota (GM) dysbiosis and multiple sclerosis (MS), fecal microbiota transplantation (FMT), aimed at rebuilding GM, has been proposed as a new therapeutic approach to MS treatment. To evaluate the viability of FMT for MS treatment and its impact on MS pathology, we tested FMT in mice with experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. We provide evidence that FMT can rectify altered GM to some extent with a therapeutic effect on EAE. We also found that FMT led to reduced activation of microglia and astrocytes and conferred protection on the blood-brain barrier (BBB), myelin, and axons in EAE. Taken together, our data suggest that FMT, as a GM-based therapy, has the potential to be an effective treatment for MS.

This new decade has started with a global pandemic of COVID-19 caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), precipitating a worldwide health crisis and economic downturn. Scientists and clinicians have been racing against time to find therapies for COVID-19. Repurposing approved drugs, developing vaccines and employing passive immunization are three major therapeutic approaches to fighting COVID-19. Chicken immunoglobulin Y (IgY) has the potential to be used as neutralizing antibody against respiratory infections, and its advantages include high avidity, low risk of adverse immune responses, and easy local delivery by intranasal administration. In this study, we raised antibody against the spike (S) protein of SARS-CoV-2 in chickens and extracted IgY (called IgY-S) from egg yolk. IgY-S exhibited high immunoreactivity against SARS-CoV-2 S, and by epitope mapping, we found five linear epitopes of IgY-S in SARS-CoV-2 S, two of which are cross-reactive with SARS-CoV S. Notably, epitope SIIAYTMSL, one of the identified epitopes, partially overlaps the S1/S2 cleavage region in SARS-CoV-2 S and is located on the surface of S trimer in 3D structure, close to the S1/S2 cleavage site. Thus, antibody binding at this location could physically block the access of proteolytic enzymes to S1/S2 cleavage site and thereby impede S1/S2 proteolytic cleavage, which is crucial to subsequent virus-cell membrane fusion and viral cell entry. Therefore, the feasibility of using IgY-S or epitope SIIAYTMS-specific IgY as neutralizing antibody for preventing or treating SARS-CoV-2 infection is worth exploring.

Oligodendrocyte precursors (OPs) proliferate and differentiate into oligodendrocytes (OLs) during postnatal development and into adulthood in the central nervous system (CNS). Following the initiation of differentiation, OPs give rise to immature, premyelinating OLs, which undergo further differentiation and mature into myelin-forming OLs. We identified an immature OL-specific long noncoding RNA, named Pcdh17it. Through co-localization analysis and morphological characterization of OLs, we found that Pcdh17it is a specific marker for newly born immature OLs in the developing and adult forebrain of mice, and we used this new marker to analyze OL generation over the lifespan of mice. Pcdh17it is an effective tool for monitoring newly born OLs in adult brain, allowing detailed study of the dynamics of OP differentiation into OLs in the normal and pathological CNS.

Myelin-gene Regulatory Factor (MyRF) is one of the master transcription factors controlling myelin formation and development in oligodendrocytes which is crucial for the powerful brain functions. The N-terminal of MyRF, which contains a proline-rich region and a DNA binding domain (DBD), is auto-cleaved from the ER membrane, and then enters the nucleus to participate in transcription regulation of the myelin genes. Here we report the crystal structure of MyRF DBD. It shows an Ig-fold like architecture which consists of two antiparallel β-sheets with 7 main strands, packing against each other, forming a β-sandwich. Compared to its homolog, Ndt80, MyRF has a smaller and less complex DBD lacking the helices and the big loops outside the core. Structural alignment reveals that MyRF DBD possess less interaction sites with DNA than Ndt80 and may bind only at the major groove of DNA. Moreover, the structure reveals a trimeric assembly, agreeing with the previous report that MyRF DBD functions as a trimer. The mutant that we designed based on the structure disturbed trimer formation, but didn’t affect the auto-cleavage reaction. It demonstrates that the activation of self-cleavage reaction of MyRF is independent of the presence of its N-terminal DBD homotrimer. The structure reported here will help to understand the molecular mechanism underlying the important roles of MyRF in myelin formation and development.

We identified mRNA encoding the ecto-enzyme Enpp6 as a marker of newly forming oligodendrocytes, and used Enpp6 in situ hybridization to track oligodendrocyte differentiation in adult mice as they learned a motor skill (running on a wheel with unevenly spaced rungs). Within just 2.5 h of exposure to the complex wheel, production of Enpp6-expressing immature oligodendrocytes was accelerated in subcortical white matter; within 4 h, it was accelerated in motor cortex. Conditional deletion of myelin regulatory factor (Myrf) in oligodendrocyte precursors blocked formation of new Enpp6(+) oligodendrocytes and impaired learning within the same ∼2-3 h time frame. This very early requirement for oligodendrocytes suggests a direct and active role in learning, closely linked to synaptic strengthening. Running performance of normal mice continued to improve over the following week accompanied by secondary waves of oligodendrocyte precursor proliferation and differentiation. We concluded that new oligodendrocytes contribute to both early and late stages of motor skill learning.

Myelin is a specialized subcellular structure that evolved uniquely in vertebrates. A myelinated axon conducts action potentials many times faster than an unmyelinated axon of the same diameter; for the same conduction speed, the unmyelinated axon would need a much larger diameter and volume than its myelinated counterpart. Hence myelin speeds information transfer and saves space, allowing the evolution of a powerful yet portable brain. Myelination in the central nervous system (CNS) is controlled by a gene regulatory program that features a number of master transcriptional regulators including Olig1, Olig2 and Myrf. Olig family genes evolved from a single ancestral gene in non-chordates. Olig2, which executes multiple functions with regard to oligodendrocyte identity and development in vertebrates, might have evolved functional versatility through post-translational modification, especially phosphorylation, as illustrated by its evolutionarily conserved serine/threonine phospho-acceptor sites and its accumulation of serine residues during more recent stages of vertebrate evolution. Olig1, derived from a duplicated copy of Olig2 in early bony fish, is involved in oligodendrocyte development and is critical to remyelination in bony vertebrates, but is lost in birds. The origin of Myrf orthologs might be the result of DNA integration between an invading phage or bacterium and an early protist, producing a fusion protein capable of self-cleavage and DNA binding. Myrf seems to have adopted new functions in early vertebrates - initiation of the CNS myelination program as well as the maintenance of mature oligodendrocyte identity and myelin structure - by developing new ways to interact with DNA motifs specific to myelin genes. This article is part of a Special Issue entitled SI: Myelin Evolution.

A novel dynamin-like GTPase gene, Pfdyn1, was cloned from an asexual stage cDNA library of Plasmodium falciparum Dd2 strain. Pfdyn1 contains a highly conserved N-terminal tripartite GTPase domain, a coiled-coil region, and a C-terminal 129 aa unknown function domain. Like yeast Vps1p, it lacks pleckstrin homology domain and proline-rich region. Western blot analysis showed that Pfdyn1 is a Triton X-100 insoluble protein expressed only in the mature sub-stage. Morphological studies indicated that Pfdyn1 is partly co-localized with PfGRP, a known ER-resident protein, and localizes diffusely with several membrane structures and a 60–100 nm vesicle both inside and on surface of the parasites and also in the cytoplasm of infected erythrocytes. The dsRNA originated by C-terminus fragment of Pfdyn1 inhibits markedly the growth of P. falciparum parasite at the erythrocyte stage. Those data showed that Pfdyn1 is a conservative, membrane related protein and plays an essential role for the survival of Plasmodium parasite.

Myelin-forming oligodendrocytes (OLs) are formed continuously in the healthy adult brain. In this work, we study the function of these late-forming cells and the myelin they produce. Learning a new motor skill (such as juggling) alters the structure of the brain’s white matter, which contains many OLs, suggesting that late-born OLs might contribute to motor learning. Consistent with this idea, we show that production of newly formed OLs is briefly accelerated in mice that learn a new skill (running on a “complex wheel” with irregularly spaced rungs). By genetically manipulating the transcription factor myelin regulatory factor in OL precursors, we blocked production of new OLs during adulthood without affecting preexisting OLs or myelin. This prevented the mice from mastering the complex wheel. Thus, generation of new OLs and myelin is important for learning motor skills.

Background Olig1 and Olig2, encoding closely related basic helix-loop-helix transcription factors, were originally identified in screens for glial-specific genes. Olig1 and Olig2 are both expressed in restricted parts of the neuroepithelium of the embryonic spinal cord and telencephalon and subsequently in oligodendrocyte lineage cells throughout life. In the spinal cord, Olig2 plays a crucial role in the development of oligodendrocytes and motor neurons, and both cell types are lost from Olig2 null mutant mice. The role of Olig1 has been more cryptic. It was initially reported that Olig1 null mice (with a Cre-Pgk-Neo cassette at the Olig1 locus) have a mild developmental phenotype characterized by a slight delay in oligodendrocyte differentiation. However, a subsequent study of the same line following removal of Pgk-Neo (leaving Olig1-Cre) found severe disruption of oligodendrocyte production, myelination failure and early postnatal lethality. A plausible explanation was proposed, that the highly expressed Pgk-Neo cassette in the original line might have up-regulated the neighbouring Olig2 gene, compensating for loss of Olig1. However, this was not tested, so the importance of Olig1 for oligodendrocyte development has remained unclear. Results We generated two independent lines of Olig1 null mice. Both lines had a mild phenotype featuring slightly delayed oligodendrocyte differentiation and maturation but no long-term effect. In addition, we found that Olig2 transcripts were not up-regulated in our Olig1 null mice. Conclusions Our findings support the original conclusion that Olig1 plays a minor and non-essential role in oligodendrocyte development and have implications for the interpretation of studies based on Olig1 deficient mice (and perhaps Olig1-Cre mice) from different sources.

Born to Stay Together For as many neurons as there are in the brain, there are many more astrocytes. These backstage workers perform a variety of functions, such as sustaining the blood-brain barrier and providing a stabilized environment for neurons. Diversity of astrocyte function is reflected in different molecular expression profiles. Tsai et al. (p. 358 , published online 28 June) selectively labeled astrocytes that originated from different domains of the mouse spinal cord and found that not all astrocytes are created equal: Neighborhoods of astrocytes were defined by shared birthplaces.

Oligodendrocyte progenitor cells (OPCs) in the postnatal mouse corpus callosum (CC) and motor cortex (Ctx) reportedly generate only oligodendrocytes (OLs), whereas those in the piriform cortex may also generate neurons. OPCs have also been subdivided based on their expression of voltage-gated ion channels, ability to respond to neuronal activity, and proliferative state. To determine whether OPCs in the piriform cortex have inherently different physiological properties from those in the CC and Ctx, we studied acute brain slices from postnatal transgenic mice in which GFP expression identifies OL lineage cells. We whole-cell patch clamped GFP-expressing (GFP + ) cells within the CC, Ctx, and anterior piriform cortex (aPC) and used prelabeling with 5-ethynyl-2′-deoxyuridine (EdU) to assess cell proliferation. After recording, slices were immunolabeled and OPCs were defined by strong expression of NG2. NG2 + OPCs in the white and gray matter proliferated and coexpressed PDGFRα and voltage-gated Na + channels (I Na ). Approximately 70% of OPCs were capable of generating regenerative depolarizations. In addition to OLIG2 + NG2 + I Na + OPCs and OLIG2 + NG2 neg I Na neg OLs, we identified cells with low levels of NG2 limited to the soma or the base of some processes. These cells had a significantly reduced I Na and a reduced ability to incorporate EdU when compared with OPCs and probably correspond to early differentiating OLs. By combining EdU labeling and lineage tracing using Pdgfrα–CreER T2 : R26R–YFP transgenic mice, we double labeled OPCs and traced their fate in the postnatal brain. These OPCs generated OLs but did not generate neurons in the aPC or elsewhere at any time that we examined.

Wnt/β-catenin signaling plays a major role in the development of the nervous system and contributes to neuronal plasticity. However, its role in myelination remains unclear. Here, we identify the Wnt/β-catenin pathway as an essential driver of myelin gene expression. The selective inhibition of Wnt components by small interfering RNA or dominant-negative forms blocks the expression of myelin protein zero (MPZ) and peripheral myelin protein 22 (PMP22) in mouse Schwann cells and proteolipid protein in mouse oligodendrocytes. Moreover, the activation of Wnt signaling by recombinant Wnt1 ligand increases by threefold the transcription of myelin genes and enhances the binding of β-catenin to T-cell factor/lymphoid-enhancer factor transcription factors present in the vicinity of the MPZ and PMP22 promoters. Most important, loss-of-function analyses in zebrafish embryos show,in vivo, a key role for Wnt/β-catenin signaling in the expression of myelin genes and in myelin sheath compaction, both in the peripheral and central nervous systems. Inhibition of Wnt/β-catenin signaling resulted in hypomyelination, without affecting Schwann cell and oligodendrocyte generation or axonal integrity. The present findings attribute to Wnt/β-catenin pathway components an essential role in myelin gene expression and myelinogenesis.

A crucial question in mammalian development is how cells of the early embryo differentiate into distinct cell types. The first decision is taken when cells undertake waves of asymmetric division that generate one daughter on the inside and one on the outside of the embryo. After this division, some cells on the inside remain pluripotent and give rise to the epiblast, and hence the future body, whereas others develop into the primitive endoderm, an extraembryonic tissue. How the fate of these inside cells is decided is unknown: Is the process random, or is it related to their developmental origins? To address this question, we traced all cells by live-cell imaging in intact, unmanipulated embryos until the epiblast and primitive endoderm became distinct. This analysis revealed that inner cell mass (ICM) cells have unrestricted developmental potential. However, cells internalized by the first wave of asymmetric divisions are biased toward forming pluripotent epiblast, whereas cells internalized in the next two waves of divisions are strongly biased toward forming primitive endoderm. Moreover, we show that cells internalized by the second wave up-regulate expression of Gata6 and Sox17, and changing the expression of these genes determines whether the cells become primitive endoderm. Finally, with our ability to determine the origin of cells, we find that inside cells that are mispositioned when they are born can sort into the correct layer. In conclusion, we propose a model in which the timing of cell internalization, cell position, and cell sorting combine to determine distinct lineages of the preimplantation mouse embryo.

One of the special attributes of vertebrates is their myelinated nervous system. By increasing the conduction velocity of axons, myelin allows for increased body size, rapid movement and a large and complex brain. In the central nervous system (CNS), oligodendrocytes (OLs) are the myelin-forming cells. The transcription factors OLIG1 and OLIG2, master regulators of OL development, presumably also played a seminal role during the evolution of the genetic programme leading to myelination in the CNS. From the available ontogenetic and phylogenetic data we attempt to reconstruct the evolutionary events that led to the emergence of the Olig gene family and speculate about the links between Olig genes, their specificcis-regulatory elements and myelin evolution. In addition, we report a putative myelin basic protein (MBP) ancestor in the lanceletBranchiostoma floridae, which lacks compact myelin. The lancelet ‘Mbp’ gene lacks the OLIG1/2- and SOX10-binding sites that characterize vertebrate Mbp homologs, raising the possibility that insertion ofcis-regulatory elements might have been involved in evolution of the myelinating programme.

Oligodendrocytes (OLs) are the myelin-forming cells of the central nervous system (CNS). They differentiate from proliferative OL precursor cells that migrate from the embryonic neuroepithelium throughout the developing CNS before associating with axons and elaborating myelin. Recent research into the regulation of OL differentiation has uncovered a two-stage mechanism of transcriptional control that combines epigenetic repression of transcriptional inhibitors with direct transcriptional activation of myelin genes. This 'two-pronged' approach creates a fail-safe system of genetic control to ensure orderly and unambiguous expression of the myelination program during development and during repair of demyelinated lesions.

The oligodendrocyte lineage genes (Olig1/2), encoding basic helix-loop-helix transcription factors, were first identified in screens for master regulators of oligodendrocyte development. OLIG1 is important for differentiation of oligodendrocyte precursors into myelin-forming oligodendrocytes during development and is thought to play a crucial role in remyelination during multiple sclerosis. However, it is still unclear how OLIG1 interacts with its transcriptional cofactors and DNA targets. OLIG1 was reportedly restricted to mammals, but we demonstrate here that zebrafish and other teleosts also possess an OLIG1 homolog. In zebrafish, as in mammals, Olig1 is expressed in the oligodendrocyte lineage. Olig1 associates physically with another myelin-associated transcription factor, Sox10, and the Olig1/Sox10 complex activatesmbp(myelin basic protein) transcription via conserved DNA sequence motifs in thembppromoter region. In contrast, Olig2 does not bind to Sox10 in zebrafish, although both OLIG1 and OLIG2 bind SOX10 in mouse.

Myelin is the multi-layered glial sheath around axons in the vertebrate nervous system. Myelinating glia develop and function in intimate association with neurons and neuron–glial interactions control much of the life history of these cells. However, many of the factors that regulate key aspects of myelin development and maintenance remain unknown. To discover new molecules that are important for glial development and myelination, we undertook a screen of zebrafish mutants with previously characterized neural defects. We screened for myelin basic protein (mbp) mRNA by in situ hybridization and identified four mutants (neckless, motionless, iguana and doc) that lacked mbp expression in parts of the peripheral and central nervous systems (PNS or CNS), despite the presence of axons. In all four mutants electron microscopy revealed that myelin-forming glia were present and had formed loose wraps around axons but did not form compact myelin. We found that addition of exogenous retinoic acid (RA) rescued mbp expression in neckless mutant embryos, which lack endogenous RA synthesis. Timed application of the RA synthesis inhibitor DEAB to wild type embryos showed that RA signalling is required at least 48 h before the onset of myelin protein synthesis in both CNS and PNS.

One size does not fit all Oligodendrocytes are best known for their ability to myelinate brain neurons, thus increasing the speed of signal transmission. Marques et al. surveyed oligodendrocytes of developing mice and found unexpected heterogeneity. Transcriptional analysis identified 12 populations, ranging from precursors to mature oligodendrocytes. Transcriptional profiles diverged as the oligodendrocytes matured, building distinct populations. One population was responsive to motor learning, and another, with a different transcriptome, traveled along blood vessels. Science , this issue p. 1326