Myelin-forming oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS) are essential for structural and functional homeostasis of nervous tissue. Albeit with certain similarities, the regulation of CNS and PNS myelination is executed differently. Recent advances highlight the coordinated regulation of oligodendrocyte myelination by amino-acid sensing and growth factor signaling pathways. In this review, we discuss novel insights into the understanding of differential regulation of oligodendrocyte and Schwann cell biology in CNS and PNS myelination, with particular focus on the roles of growth factor-stimulated RHEB-mTORC1 and GATOR2-mediated amino-acid sensing/signaling pathways. We also discuss recent progress on the metabolic regulation of oligodendrocytes and Schwann cells and the impact of their dysfunction on neuronal function and disease.
Amino Acids ; Myelin Sheath/metabolism* ; Schwann Cells/metabolism* ; Oligodendroglia/metabolism* ; Signal Transduction ; Intercellular Signaling Peptides and Proteins/metabolism*

Enhancing remyelination after injury is of utmost importance for optimizing the recovery of nerve function. While the formation of myelin by Schwann cells (SCs) is critical for the function of the peripheral nervous system, the temporal dynamics and regulatory mechanisms that control the progress of the SC lineage through myelination require further elucidation. Here, using in vitro co-culture models, gene expression profiling of laser capture-microdissected SCs at various stages of myelination, and multilevel bioinformatic analysis, we demonstrated that SCs exhibit three distinct transcriptional characteristics during myelination: the immature, promyelinating, and myelinating states. We showed that suppressor interacting 3a (Sin3A) and 16 other transcription factors and chromatin regulators play important roles in the progress of myelination. Sin3A knockdown in the sciatic nerve or specifically in SCs reduced or delayed the myelination of regenerating axons in a rat crushed sciatic nerve model, while overexpression of Sin3A greatly promoted the remyelination of axons. Further, in vitro experiments revealed that Sin3A silencing inhibited SC migration and differentiation at the promyelination stage and promoted SC proliferation at the immature stage. In addition, SC differentiation and maturation may be regulated by the Sin3A/histone deacetylase2 (HDAC2) complex functionally cooperating with Sox10, as demonstrated by rescue assays. Together, these results complement the recent genome and proteome analyses of SCs during peripheral nerve myelin formation. The results also reveal a key role of Sin3A-dependent chromatin organization in promoting myelinogenic programs and SC differentiation to control peripheral myelination and repair. These findings may inform new treatments for enhancing remyelination and nerve regeneration.
Animals ; Axons ; Chromatin/metabolism* ; Gene Expression Profiling ; Myelin Sheath/metabolism* ; Nerve Regeneration/physiology* ; Rats ; Schwann Cells/metabolism* ; Sciatic Nerve/injuries*

OBJECTIVE: To investigate the role of myelin and lymphocyte protein (MAL) in pulmonary hypertension (PAH). METHODS: Blood samples were collected from 50 patients with PAH (PAH group) and 50 healthy individuals for detection of plasma MAL expression using ELISA.According to the echocardiographic findings, the patients were divided into moderate/severe group (n=18) and mild group (n=32), and the correlation between MAL protein level and the severity of PAH was analyzed.In a pulmonary artery smooth muscle cell model of PAH with hypoxia-induced abnormal proliferation, the effects of mal gene knockdown and overexpression on cell growth, proliferation and starvation-induced apoptosis were observed; the changes in NK-κB signaling pathway in the transfected cells were detected to explore the molecular mechanism by which MAL regulates PAMSC proliferation and apoptosis. RESULTS: The plasma level of MAL was significantly higher in patients with PAH than in healthy individuals (P < 0.05), and the patients with moderate/severe PAH had significantly higher MAL level than those with mild PAH (P < 0.001).In PAMSCs, exposure to hypoxia significantly increased the mRNA and protein expression levels of MAL (P < 0.05), and MAL knockdown obviously inhibited hypoxia-induced proliferation and promoted starvation-induced apoptosis of the PAMSCs (P < 0.05).Knocking down mal significantly inhibited the activation of NK-κB signaling pathway that participated in regulation of PAMSC proliferation (P < 0.05). CONCLUSION The plasma level of MAL is elevated in PAH patients in positive correlation with the disease severity.MAL knockdown inhibits abnormal proliferation and promotes apoptosis of PAMSCs by targeted inhibition of the NF-κB signaling pathway to improve vascular remodeling in PAH.
Humans ; Pulmonary Artery ; Hypertension, Pulmonary ; Myelin Sheath/metabolism* ; Apoptosis ; Myocytes, Smooth Muscle ; Vascular Remodeling/genetics* ; Cell Proliferation ; Hypoxia/metabolism* ; Lymphocytes

The exacerbation of progressive multiple sclerosis (MS) is closely associated with obstruction of the differentiation of oligodendrocyte progenitor cells (OPCs). To discover novel therapeutic compounds for enhancing remyelination by endogenous OPCs, we screened for myelin basic protein expression using cultured rat OPCs and a library of small-molecule compounds. One of the most effective drugs was pinocembrin, which remarkably promoted OPC differentiation and maturation without affecting cell proliferation and survival. Based on these in vitro effects, we further assessed the therapeutic effects of pinocembrin in animal models of demyelinating diseases. We demonstrated that pinocembrin significantly ameliorated the progression of experimental autoimmune encephalomyelitis (EAE) and enhanced the repair of demyelination in lysolectin-induced lesions. Further studies indicated that pinocembrin increased the phosphorylation level of mammalian target of rapamycin (mTOR). Taken together, our results demonstrated that pinocembrin promotes OPC differentiation and remyelination through the phosphorylated mTOR pathway, and suggest a novel therapeutic prospect for this natural flavonoid product in treating demyelinating diseases.
Animals ; Cell Differentiation ; Flavanones ; Mice ; Mice, Inbred C57BL ; Myelin Sheath/metabolism* ; Oligodendroglia/metabolism* ; Rats ; Remyelination ; Signal Transduction ; TOR Serine-Threonine Kinases/metabolism*

Oligodendrocytes (OLs) are myelinating glial cells that form myelin sheaths around axons to ensure rapid and focal conduction of action potentials. Here, we found that an axonal outgrowth regulatory molecule, AATYK (apoptosis-associated tyrosine kinase), was up-regulated with OL differentiation and remyelination. We therefore studied its role in OL differentiation. The results showed that AATYK knockdown inhibited OL differentiation and the expression of myelin genes in vitro. Moreover, AATYK-deficiency maintained the proliferation status of OLs but did not affect their survival. Thus, AATYK is essential for the differentiation of OLs.
Animals ; Animals, Newborn ; Apoptosis Regulatory Proteins ; genetics ; metabolism ; Cell Differentiation ; drug effects ; physiology ; Cell Proliferation ; drug effects ; genetics ; Cells, Cultured ; Cuprizone ; toxicity ; Demyelinating Diseases ; chemically induced ; metabolism ; pathology ; Embryo, Mammalian ; Gene Expression Regulation, Developmental ; genetics ; Ki-67 Antigen ; metabolism ; Mice ; Mice, Inbred C57BL ; Myelin Basic Protein ; metabolism ; Myelin Proteolipid Protein ; metabolism ; Myelin Sheath ; drug effects ; metabolism ; Oligodendroglia ; drug effects ; metabolism ; Protein-Tyrosine Kinases ; genetics ; metabolism ; RNA, Small Interfering ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley

Emerging evidence indicates that microglia activation plays an important role in spinal cord injury (SCI) caused by trauma. Studies have found that inhibiting the Rho/Rho-associated protein kinase (ROCK) signaling pathway can reduce inflammatory cytokine production by microglia. In this study, Western blotting was conducted to detect ROCK2 expression after the SCI; the ROCK Activity Assay kit was used for assay of ROCK pathway activity; microglia morphology was examined using the CD11b antibody; electron microscopy was used to detect microglia phagocytosis; TUNEL was used to detect tissue cell apoptosis; myelin staining was performed using an antibody against myelin basic protein (MBP); behavioral outcomes were evaluated according to the methods of Basso, Beattie, and Bresnahan (BBB). We observed an increase in ROCK activity and microglial activation after SCI. The microglia became larger and rounder and contained myelin-like substances. Furthermore, treatment with fasudil inhibited neuronal cells apoptosis, alleviated demyelination and the formation of cavities, and improved motor recovery. The experimental evidence reveals that the ROCK inhibitor fasudil can regulate microglial activation, promote cell phagocytosis, and improve the SCI microenvironment to promote SCI repair. Thus, fasudil may be useful for the treatment of SCI.
1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; analogs & derivatives ; pharmacology ; therapeutic use ; Animals ; Apoptosis ; Male ; Microglia ; drug effects ; metabolism ; Myelin Basic Protein ; metabolism ; Myelin Sheath ; metabolism ; Phagocytosis ; Protein Kinase Inhibitors ; pharmacology ; therapeutic use ; Rats ; Rats, Sprague-Dawley ; Spinal Cord Injuries ; drug therapy ; rho-Associated Kinases ; antagonists & inhibitors ; metabolism

OBJECTIVETo study in vivo the endogenous self-repair mechanism in immature white matter induced by ischemia in neonatal rats with periventricular leukomalacia (PVL).

METHODSFive-day-old neonatal Sprague-Dawley (SD) rats were randomly divided into sham and PVL groups. Rat model of PVL was prepared by ligation of the right common carotid artery following 2 hours of exposure to 8% oxygen. Pathological changes and myelination in the white matter were assessed under light and electron microscopy at 7 and 21 days after PVL. O4-positive OL precursor cells in the white matter were determined with immunofluorescence staining. Activation, proliferation, migration and differentiation of glial progenitor cells in SVZ were observed using immunofluorescent double labeling of either NG2 (marker of progenitor cells) and 5-bromodeoxyuridine (BrdU), or O4 (marker of OL precursor cells) and BrdU.

RESULTSAll rats in the PVL group manifested either mild or severe white matter injury under light microscopy, and had higher pathological scores of white matter compared with the sham group at 7 and 21 days after PVL (P<0.05). Electron microscopy showed that the number and thickness of myelin sheath in the PVL group were significantly reduced compared with the sham group (P<0.01). O4-positive OL precursor cells in the white matter observed under fluorescence microscopy were significantly reduced in the PVL group compared with the sham group (P<0.05). BrdU/NG2-positive cells in the SVZ increased significantly in the PVL group 48 hours after PVL and migrated into the periventricular area, reaching a peak on day 7 after PVL. BrdU/O4-positive newborn cells began to appear in the periventricular area 72 hours after PVL, and the number of BrdU/O4-positive cells in the PVL group was statistically more than in the sham group on day 21 after PVL (P<0.05).

CONCLUSIONSIschemia may induce brain self-repair in neonatal rats, resulting in activation and proliferation of NG2 glial progenitor cells in the SVZ migration and differentiation into OL precursor cells in periventricular white matter.

Animals ; Animals, Newborn ; Brain ; pathology ; Brain Ischemia ; pathology ; Bromodeoxyuridine ; metabolism ; Cell Differentiation ; Disease Models, Animal ; Humans ; Infant, Newborn ; Leukomalacia, Periventricular ; pathology ; Myelin Sheath ; physiology ; Neuroglia ; pathology ; Rats ; Rats, Sprague-Dawley ; Stem Cells ; pathology

Schizophrenia is likely to be a multifactorial disorder, consequence of alterations in gene and protein expression since the neurodevelopment that together to environmental factors will trigger the establishment of the disease. In the post-genomic era, proteomics has emerged as a promising strategy for revealing disease and treatment biomarkers as well as a tool for the comprehension of the mechanisms of schizophrenia pathobiology. Here, there is a discussion of the potential pathways and structures that are compromised in schizophrenia according to proteomic findings while studying five distinct brain regions of post-mortem tissue from schizophrenia patients and controls. Proteins involved in energy metabolism, calcium homeostasis, myelinization, and cytoskeleton have been recurrently found to be differentially expressed in schizophrenia brains. These findings may encourage new studies on the understanding of schizophrenia biochemical pathways and even new potential drug targets.
Biomarkers ; Brain ; Calcium ; Comprehension ; Cytoskeleton ; Energy Metabolism ; Homeostasis ; Humans ; Myelin Sheath ; Oligodendroglia ; Proteins ; Proteomics ; Schizophrenia

Endothelin (ET)-1 and its receptors (ETA and ETB receptor) are present in the central nervous system. ET exerts biological effects on gliogenesis and glial cell functions. In order to define a possible mechanism of ETA receptor signaling, the distribution of the ETA receptor in developing oligodendrocytes and the effects of ET-1 on the myelination of oligodendrocytes were examined. ETA receptor immunoreactivity was confined to the perivascular elements of the blood vessels during early postnatal development. However later in development, ETA receptor immunoreactivity was no longer observed in the vessels but became localized to the myelinating oligodendrocytes of the primitive corpus callosum of the white matter, apart from the vessels. ET-1 induced myelin basic protein (MBP) in primary oligodendrocyte precursor cell culture though the ETA receptor and was blocked by an ETA receptor antagonist. In addition, ET-1 evoked the release of Ca2+ which is a central regulator of oligodendrocyte differentiation. Our results provide a link between ET-1 and its ETA receptor and myelination during oligodendrocyte differentiation.
Animals ; Brain/pathology ; Calcium/metabolism ; Calcium Signaling ; Cells, Cultured ; Endothelin-1/metabolism/physiology ; Mice ; Mice, Inbred ICR ; Myelin Basic Proteins/genetics/metabolism ; Myelin Sheath/*physiology ; Oligodendroglia/cytology/*metabolism ; Rats ; Rats, Sprague-Dawley ; Receptor, Endothelin A/metabolism/*physiology

PURPOSE: This study was performed to describe the ultrastructure of stromal nerve fibers in central, mid-peripheral, and peripheral parts of the human cornea by flat serial corneal section. METHODS: Seven samples from fresh normal cornea, derived from eyes with retinoblastoma and eyes from eye bank, were processed for transmission electron microscopic examinations. Flat serial sections reaching from mid-epithelium to the anterior stroma were observed. RESULTS: The myelinated and unmyelinated nerve fibers are alternately arranged and run parallel to the stromal collagen fibers at the periphery of the cornea. The main difference between the limbal and the central cornea is the presence of myelinated nerve fibers in the anterior peripheral stroma. The diameter of the unmyelinated nerve fiber measures between 0.25 and 0.63 micrometer in size. The corneal nerve fibers contain vesicles, mitochondria, and glycogen particles. The peripheral nerve fibers contain both clear and dense vesicles. The nerve fiber is separated by an interval of 0.3 micrometer from the cytoplasmic wall of keratocyte at the center of the cornea. CONCLUSIONS: The majority of the corneal nerve fibers can be classified as C-fibers due to their size. The presence of both clear and dense vesicles within the cytoplasm of the periphery of the cornea suggest that a small portion in the peripheral corneal nerve may be originated from the sympathetic nervous system. A close vicinity between the nerve fibers and keratocyte supports that nerve fibers might modulate the release of growth factors in the regulation of stromal and epithelial metabolism.
Collagen ; Cornea ; Cytoplasm ; Eye Banks ; Glycogen ; Humans ; Intercellular Signaling Peptides and Proteins ; Metabolism ; Mitochondria ; Myelin Sheath ; Nerve Fibers ; Nerve Fibers, Myelinated ; Nerve Fibers, Unmyelinated ; Peripheral Nerves ; Retinoblastoma ; Sympathetic Nervous System