Schwann Cell Development and Myelination.

Glial cells in the peripheral nervous system (PNS), which arise from the neural crest, include axon-associated Schwann cells (SCs) in nerves, synapse-associated SCs at the neuromuscular junction, enteric glia, perikaryon-associated satellite cells in ganglia, and boundary cap cells at the border between the central nervous system (CNS) and the PNS. Here, we focus on axon-associated SCs. These SCs progress through a series of formative stages, which culminate in the generation of myelinating SCs that wrap large-caliber axons and of nonmyelinating (Remak) SCs that enclose multiple, small-caliber axons. In this work, we describe SC development, extrinsic signals from the axon and extracellular matrix (ECM) and the intracellular signaling pathways they activate that regulate SC development, and the morphogenesis and organization of myelinating SCs and the myelin sheath. We review the impact of SCs on the biology and integrity of axons and their emerging role in regulating peripheral nerve architecture. Finally, we explain how transcription and epigenetic factors control and fine-tune SC development and myelination.

NECAB2 is an endosomal protein important for striatal function.

Synaptic signaling depends on ATP generated by mitochondria. Dysfunctional mitochondria shift the redox balance towards a more oxidative environment. Due to extensive connectivity, the striatum is especially vulnerable to mitochondrial dysfunction. We found that neuronal calcium-binding protein 2 (NECAB2) plays a role in striatal function and mitochondrial homeostasis. NECAB2 is a predominantly endosomal striatal protein which partially colocalizes with mitochondria. This colocalization is enhanced by mild oxidative stress. Global knockout of Necab2 in the mouse results in increased superoxide levels, increased DNA oxidation and reduced levels of the antioxidant glutathione which correlates with an altered mitochondrial shape and function. Striatal mitochondria from Necab2 knockout mice are more abundant and smaller and characterized by a reduced spare capacity suggestive of intrinsic uncoupling respectively mitochondrial dysfunction. In line with this, we also found an altered stress-induced interaction of endosomes with mitochondria in Necab2 knockout striatal cultures. The predominance of dysfunctional mitochondria and the pro-oxidative redox milieu correlates with a loss of striatal synapses and behavioral changes characteristic of striatal dysfunction like reduced motivation and altered sensory gating. Together this suggests an involvement of NECAB2 in an endosomal pathway of mitochondrial stress response important for striatal function.

Joint manifestations revealing inborn metabolic diseases in adults: a narrative review.

Inborn metabolic diseases (IMD) are rare conditions that can be diagnosed during adulthood. Patients with IMD may have joint symptoms and the challenge is to establish an early diagnosis in order to institute appropriate treatment and prevent irreversible damage. This review describes the joint manifestations of IMD that may be encountered in adults. The clinical settings considered were arthralgia and joint stiffness as well as arthritis. Unspecific arthralgias are often the first symptoms of hereditary hemochromatosis, chronic low back pain may reveal an intervertebral disc calcification in relation with alkaptonuria, and progressive joint stiffness may correspond to a mucopolysaccharidosis or mucolipidosis. Gaucher disease is initially revealed by painful acute attacks mimicking joint pain described as "bone crises". Some IMD may induce microcrystalline arthropathy. Beyond classical gout, there are also gouts in connection with purine metabolism disorders known as "enzymopathic gouts". Pyrophosphate arthropathy can also be part of the clinical spectrum of Gitelman syndrome or hypophosphatasia. Oxalate crystals arthritis can reveal a primary hyperoxaluria. Destructive arthritis may be indicative of Wilson's disease. Non-destructive arthritis may be seen in mevalonate kinase deficiency and familial hypercholesterolemia.

Mechanisms of Demyelination and Remyelination Strategies for Multiple Sclerosis.

All currently licensed medications for multiple sclerosis (MS) target the immune system. Albeit promising preclinical results demonstrated disease amelioration and remyelination enhancement via modulating oligodendrocyte lineage cells, most drug candidates showed only modest or no effects in human clinical trials. This might be due to the fact that remyelination is a sophistically orchestrated process that calls for the interplay between oligodendrocyte lineage cells, neurons, central nervous system (CNS) resident innate immune cells, and peripheral immune infiltrates and that this process may somewhat differ in humans and rodent models used in research. To ensure successful remyelination, the recruitment and activation/repression of each cell type should be regulated in a highly organized spatio-temporal manner. As a result, drug candidates targeting one single pathway or a single cell population have difficulty restoring the optimal microenvironment at lesion sites for remyelination. Therefore, when exploring new drug candidates for MS, it is instrumental to consider not only the effects on all CNS cell populations but also the optimal time of administration during disease progression. In this review, we describe the dysregulated mechanisms in each relevant cell type and the disruption of their coordination as causes of remyelination failure, providing an overview of the complex cell interplay in CNS lesion sites.

Mechanisms and treatment strategies of demyelinating and dysmyelinating Charcot-Marie-Tooth disease.

Schwann cells, the myelinating glia of the peripheral nervous system, wrap axons multiple times to build their myelin sheath. Myelin is of paramount importance for axonal integrity and fast axon potential propagation. However, myelin is lacking or dysfunctional in several neuropathies including demyelinating and dysmyelinating Charcot-Marie-Tooth disease. Charcot-Marie-Tooth disease represents the most prevalent inherited neuropathy in humans and is classified either as axonal, demyelinating or dysmyelinating, or as intermediate. The demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease constitute the majority of the disease cases and are most frequently due to mutations in the three following myelin genes: peripheral myelin protein 22, myelin protein zero and gap junction beta 1 (coding for Connexin 32) causing Charcot-Marie-Tooth disease type 1A, Charcot-Marie-Tooth disease type 1B, and X-linked Charcot-Marie-Tooth disease type 1, respectively. The resulting perturbation of myelin structure and function leads to axonal demyelination or dysmyelination and causes severe disabilities in affected patients. No treatment to cure or slow down the disease progression is currently available on the market, however, scientific discoveries led to a better understanding of the pathomechanisms of the disease and to potential treatment strategies. In this review, we describe the features and molecular mechanisms of the three main demyelinating or dysmyelinating forms of Charcot-Marie-Tooth disease, the rodent models used in research, and the emerging therapeutic approaches to cure or counteract the progression of the disease.

Discharge of newborns with risk factors of severe hyperbilirubinemia: description of a hospital at home-based care monitoring and phototherapy.

Neonatal jaundice is common and associated with delay in hospital discharge and risk of neurological sequelae if not treated. The objectives of the study were to report on our experience of the monitoring and treatment of neonatal jaundice in a home care setting and its feasibility and safety for neonates with high risk of severe hyperbilirubinemia. The 2-year study has been led in the greater Paris University Hospital At Home (Assistance Publique-Hôpitaux de Paris). The device of the intervention was the Bilicocoon® Bag, a light-emitting diode sleeping bag worn by the neonate when the total serum bilirubin value exceeds intensive phototherapy threshold, according to the guidelines from the American Academy of Pediatrics. One hundred and thirty-nine neonates had participated in the intervention and 39 (28%) were treated by phototherapy at home, as continuation of inpatient phototherapy or started at home. Seventy-five percent of the sample had more than two risk factors for development of severe hyperbilirubinemia. Twenty five percent of the cohort who received phototherapy at home had lower gestational age (p < 0.014) and had younger age at discharge from maternity (p < 0.09). Median length of stay in hospital at home was 5 days. Two patients needed readmission in conventional hospital (1%) for less than 24 h. In multivariate model, the length of stay decreased with the higher gestational age (p < 0.001) and increased significantly with the older age at discharge, the birth weight < 10th percentile, and a treatment by phototherapy at home.    Conclusion: Hospital at home, which is a whole strategy using an effective and convenient phototherapy device combined with a specialized medical follow-up, could be an alternative to conventional hospitalization for neonates at high risk of severe jaundice. The maternity discharge is facilitated, the mother-infant bonding can be promoted, and the risk of conventional rehospitalization is minimal, while guaranteeing the safety of this specific care. What is Known: • Managing neonatal jaundice is provided in conventional hospital with phototherapy. • Neonatal jaundice increases the risk of prolonged hospitalization or readmission. What is New: • Phototherapy is feasible in hospital at home for neonates with high risk of severe hyperbilirubinemia. • The care pathway of neonates from conventional hospital to hospital at home is described.

Theophylline Induces Remyelination and Functional Recovery in a Mouse Model of Peripheral Neuropathy.

Charcot-Marie-Tooth disease (CMT) is a large group of inherited peripheral neuropathies that are primarily due to demyelination and/or axonal degeneration. CMT type 1A (CMT1A), which is caused by the duplication of the peripheral myelin protein 22 (PMP22) gene, is a demyelinating and the most frequent CMT subtype. Hypermyelination, demyelination, and secondary loss of large-caliber axons are hallmarks of CMT1A, and there is currently no cure and no efficient treatment to alleviate the symptoms of the disease. We previously showed that histone deacetylases 1 and 2 (HDAC1/2) are critical for Schwann cell developmental myelination and remyelination after a sciatic nerve crush lesion. We also demonstrated that a short-term treatment with Theophylline, which is a potent activator of HDAC2, enhances remyelination and functional recovery after a sciatic nerve crush lesion in mice. In the present study, we tested whether Theophylline treatment could also lead to (re)myelination in a PMP22-overexpressing mouse line (C22) modeling CMT1A. Indeed, we show here that a short-term treatment with Theophylline in C22 mice increases the percentage of myelinated large-caliber axons and the expression of the major peripheral myelin protein P0 and induces functional recovery. This pilot study suggests that Theophylline treatment could be beneficial to promote myelination and thereby prevent axonal degeneration and enhance functional recovery in CMT1A patients.

EEF1A1 deacetylation enables transcriptional activation of remyelination.

Remyelination of the peripheral and central nervous systems (PNS and CNS, respectively) is a prerequisite for functional recovery after lesion. However, this process is not always optimal and becomes inefficient in the course of multiple sclerosis. Here we show that, when acetylated, eukaryotic elongation factor 1A1 (eEF1A1) negatively regulates PNS and CNS remyelination. Acetylated eEF1A1 (Ac-eEF1A1) translocates into the nucleus of myelinating cells where it binds to Sox10, a key transcription factor for PNS and CNS myelination and remyelination, to drag Sox10 out of the nucleus. We show that the lysine acetyltransferase Tip60 acetylates eEF1A1, whereas the histone deacetylase HDAC2 deacetylates eEF1A1. Promoting eEF1A1 deacetylation maintains the activation of Sox10 target genes and increases PNS and CNS remyelination efficiency. Taken together, these data identify a major mechanism of Sox10 regulation, which appears promising for future translational studies on PNS and CNS remyelination.

Mechanisms of Schwann cell plasticity involved in peripheral nerve repair after injury.

The great plasticity of Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), is a critical feature in the context of peripheral nerve regeneration following traumatic injuries and peripheral neuropathies. After a nerve damage, SCs are rapidly activated by injury-induced signals and respond by entering the repair program. During the repair program, SCs undergo dynamic cell reprogramming and morphogenic changes aimed at promoting nerve regeneration and functional recovery. SCs convert into a repair phenotype, activate negative regulators of myelination and demyelinate the damaged nerve. Moreover, they express many genes typical of their immature state as well as numerous de-novo genes. These genes modulate and drive the regeneration process by promoting neuronal survival, damaged axon disintegration, myelin clearance, axonal regrowth and guidance to their former target, and by finally remyelinating the regenerated axon. Many signaling pathways, transcriptional regulators and epigenetic mechanisms regulate these events. In this review, we discuss the main steps of the repair program with a particular focus on the molecular mechanisms that regulate SC plasticity following peripheral nerve injury.

Functions of histone modifications and histone modifiers in Schwann cells.

Schwann cells (SCs) are the main glial cells present in the peripheral nervous system (PNS). Their primary functions are to insulate peripheral axons to protect them from the environment and to enable fast conduction of electric signals along big caliber axons by enwrapping them in a thick myelin sheath rich in lipids. In addition, SCs have the peculiar ability to foster axonal regrowth after a lesion by demyelinating and converting into repair cells that secrete neurotrophic factors and guide axons back to their former target to finally remyelinate regenerated axons. The different steps of SC development and their role in the maintenance of PNS integrity and regeneration after lesion are controlled by various factors among which transcription factors and chromatin-remodeling enzymes hold major functions. In this review, we discussed how histone modifications and histone-modifying enzymes control SC development, maintenance of PNS integrity and response to injury. The functions of histone modifiers as part of chromatin-remodeling complexes are discussed in another review published in the same issue of Glia.

Injured Axons Instruct Schwann Cells to Build Constricting Actin Spheres to Accelerate Axonal Disintegration.

After a peripheral nerve lesion, distal ends of injured axons disintegrate into small fragments that are subsequently cleared by Schwann cells and later by macrophages. Axonal debris clearing is an early step of the repair process that facilitates regeneration. We show here that Schwann cells promote distal cut axon disintegration for timely clearing. By combining cell-based and in vivo models of nerve lesion with mouse genetics, we show that this mechanism is induced by distal cut axons, which signal to Schwann cells through PlGF mediating the activation and upregulation of VEGFR1 in Schwann cells. In turn, VEGFR1 activates Pak1, leading to the formation of constricting actomyosin spheres along unfragmented distal cut axons to mediate their disintegration. Interestingly, oligodendrocytes can acquire a similar behavior as Schwann cells by enforced expression of VEGFR1. These results thus identify controllable molecular cues of a neuron-glia crosstalk essential for timely clearing of damaged axons.

Novel KDM5B splice variants identified in patients with developmental disorders: Functional consequences.

Histone lysine methylation influences processes such as gene expression and DNA repair. Thirty Jumonji C (JmjC) domain-containing proteins have been identified and phylogenetically clustered into seven subfamilies. Most JmjC domain-containing proteins have been shown to possess histone demethylase activity toward specific histone methylation marks. One of these subfamilies, the KDM5 family, is characterized by five conserved domains and includes four members. Interestingly, de novo loss-of-function and missense variants in KDM5B were identified in patients with intellectual disability (ID) and autism spectrum disorder (ASD) but also in unaffected individuals. Here, we report two novel de novo splice variants in the KDM5B gene in three patients with ID and ASD. The c.808 + 1G > A variant was identified in a boy with mild ID and autism traits and is associated with a significant reduced KDM5B mRNA expression without alteration of its H3K4me3 pattern. In contrast, the c.576 + 2T > C variant was found in twins with global delay in developmental milestones, poor language and ASD. This variant causes the production of an abnormal transcript which may produce an altered protein with the loss of the ARID1B domain with an increase in global gene H3K4me3. Our data reinforces the recent observation that the KDM5B haploinsufficiency is not a mechanism involved in intellectual disability and that KDM5B disorder associated with LOF variants is a recessive disorder. However, some variants may also cause gain of function, and need to be interpreted with caution, and functional studies should be performed to identify the molecular consequences of these different rare variants.

Modeling PNS and CNS Myelination Using Microfluidic Chambers.

Modeling myelination in vitro allows mechanistic study of developmental myelination and short-term myelin maintenance, but analyses possible to carry out using currently available models are usually limited because of high cell density and the lack of separation between neurons and myelinating cells. Furthermore, regeneration studies of myelinated systems after lesion require compartmentalization of neuronal cell bodies, axons, and myelinating cells. Here we describe a compartmentalized method using microfluidics that allows live-cell imaging at the single-cell level to follow short- and long-term dynamic interactions of neurons and myelinating cells and large-scale analyses, e.g., RNA sequencing on pure or highly enriched neurons or myelinating cells, separately.

Chromatin-remodeling enzymes in control of Schwann cell development, maintenance and plasticity.

Gene regulation is essential for cellular differentiation and plasticity. Schwann cells (SCs), the myelinating glia of the peripheral nervous system (PNS), develop from neural crest cells to mature myelinating SCs and can at early developmental stage differentiate into various cell types. After a PNS lesion, SCs can also convert into repair cells that guide and stimulate axonal regrowth, and remyelinate regenerated axons. What controls their development and versatile nature? Several recent studies highlight the key roles of chromatin modifiers in these processes, allowing SCs to regulate their gene expression profile and thereby acquire or change their identity and quickly react to their environment.

Delaying histone deacetylase response to injury accelerates conversion into repair Schwann cells and nerve regeneration.

The peripheral nervous system (PNS) regenerates after injury. However, regeneration is often compromised in the case of large lesions, and the speed of axon reconnection to their target is critical for successful functional recovery. After injury, mature Schwann cells (SCs) convert into repair cells that foster axonal regrowth, and redifferentiate to rebuild myelin. These processes require the regulation of several transcription factors, but the driving mechanisms remain partially understood. Here we identify an early response to nerve injury controlled by histone deacetylase 2 (HDAC2), which coordinates the action of other chromatin-remodelling enzymes to induce the upregulation of Oct6, a key transcription factor for SC development. Inactivating this mechanism using mouse genetics allows earlier conversion into repair cells and leads to faster axonal regrowth, but impairs remyelination. Consistently, short-term HDAC1/2 inhibitor treatment early after lesion accelerates functional recovery and enhances regeneration, thereby identifying a new therapeutic strategy to improve PNS regeneration after lesion.

Mature lipid droplets are accessible to ER luminal proteins.

Lipid droplets are found in most organisms where they serve to store energy in the form of neutral lipids. They are formed at the endoplasmic reticulum (ER) membrane where the neutral-lipid-synthesizing enzymes are located. Recent results indicate that lipid droplets remain functionally connected to the ER membrane in yeast and mammalian cells to allow the exchange of both lipids and integral membrane proteins between the two compartments. The precise nature of the interface between the ER membrane and lipid droplets, however, is still ill-defined. Here, we probe the topology of lipid droplet biogenesis by artificially targeting proteins that have high affinity for lipid droplets to inside the luminal compartment of the ER. Unexpectedly, these proteins still localize to lipid droplets in both yeast and mammalian cells, indicating that lipid droplets are accessible from within the ER lumen. These data are consistent with a model in which lipid droplets form a specialized domain in the ER membrane that is accessible from both the cytosolic and the ER luminal side.

HDAC1/2-Dependent P0 Expression Maintains Paranodal and Nodal Integrity Independently of Myelin Stability through Interactions with Neurofascins.

The pathogenesis of peripheral neuropathies in adults is linked to maintenance mechanisms that are not well understood. Here, we elucidate a novel critical maintenance mechanism for Schwann cell (SC)-axon interaction. Using mouse genetics, ablation of the transcriptional regulators histone deacetylases 1 and 2 (HDAC1/2) in adult SCs severely affected paranodal and nodal integrity and led to demyelination/remyelination. Expression levels of the HDAC1/2 target gene myelin protein zero (P0) were reduced by half, accompanied by altered localization and stability of neurofascin (NFasc)155, NFasc186, and loss of Caspr and septate-like junctions. We identify P0 as a novel binding partner of NFasc155 and NFasc186, both in vivo and by in vitro adhesion assay. Furthermore, we demonstrate that HDAC1/2-dependent P0 expression is crucial for the maintenance of paranodal/nodal integrity and axonal function through interaction of P0 with neurofascins. In addition, we show that the latter mechanism is impaired by some P0 mutations that lead to late onset Charcot-Marie-Tooth disease.

Transcriptional control of neural crest specification into peripheral glia.

The neural crest is a transient migratory multipotent cell population that originates from the neural plate border and is formed at the end of gastrulation and during neurulation in vertebrate embryos. These cells give rise to many different cell types of the body such as chondrocytes, smooth muscle cells, endocrine cells, melanocytes, and cells of the peripheral nervous system including different subtypes of neurons and peripheral glia. Acquisition of lineage-specific markers occurs before or during migration and/or at final destination. What are the mechanisms that direct specification of neural crest cells into a specific lineage and how do neural crest cells decide on a specific migration route? Those are fascinating and complex questions that have existed for decades and are still in the research focus of developmental biologists. This review discusses transcriptional events and regulations occurring in neural crest cells and derived lineages, which control specification of peripheral glia, namely Schwann cell precursors that interact with peripheral axons and further differentiate into myelinating or nonmyelinating Schwann cells, satellite cells that remain tightly associated with neuronal cell bodies in sensory and autonomous ganglia, and olfactory ensheathing cells that wrap olfactory axons, both at the periphery in the olfactory mucosa and in the central nervous system in the olfactory bulb. Markers of the different peripheral glia lineages including intermediate multipotent cells such as boundary cap cells, as well as the functions of these specific markers, are also reviewed. Enteric ganglia, another type of peripheral glia, will not be discussed in this review. GLIA 2015;63:1883-1896.

HDAC1 and HDAC2 control the specification of neural crest cells into peripheral glia.

Schwann cells, the myelinating glia of the peripheral nervous system (PNS), originate from multipotent neural crest cells that also give rise to other cells, including neurons, melanocytes, chondrocytes, and smooth muscle cells. The transcription factor Sox10 is required for peripheral glia specification. However, all neural crest cells express Sox10 and the mechanisms directing neural crest cells into a specific lineage are poorly understood. We show here that histone deacetylases 1 and 2 (HDAC1/2) are essential for the specification of neural crest cells into Schwann cell precursors and satellite glia, which express the early determinants of their lineage myelin protein zero (P0) and/or fatty acid binding protein 7 (Fabp7). In neural crest cells, HDAC1/2 induced expression of the transcription factor Pax3 by binding and activating the Pax3 promoter. In turn, Pax3 was required to maintain high Sox10 levels and to trigger expression of Fabp7. In addition, HDAC1/2 were bound to the P0 promoter and activated P0 transcription. Consistently, in vivo genetic deletion of HDAC1/2 in mouse neural crest cells led to strongly decreased Sox10 expression, no detectable Pax3, virtually no satellite glia, and no Schwann cell precursors in dorsal root ganglia and peripheral nerves. Similarly, in vivo ablation of Pax3 in the mouse neural crest resulted in strongly reduced expression of Sox10 and Fabp7. Therefore, by controlling the expression of Pax3 and the concerted action of Pax3 and Sox10 on their target genes, HDAC1/2 direct the specification of neural crest cells into peripheral glia.