Myelin-Associated Glycoprotein Is a Myelin Signal that Modulates the Caliber of Myelinated Axons

Yin, Xiaoju; Crawford, Thomas O.; Griffin, John W.; Tu, Pang Hsien; Lee, Virginia M.‐Y.; Li, Chumei; Roder, John; Trapp, Bruce D.

doi:10.1523/jneurosci.18-06-01953.1998

Cited by 442 publications

(395 citation statements)

References 47 publications

(61 reference statements)

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“…17 In vivo experiments support this hypothesis, as the disruption of myelin genome in mice results in late-onset axonal degeneration without significant myelin pathology. 18,19 These findings strengthen the hypothesis that long-term axonal survival requires trophic support from oligodendrocytes, possibly independent of myelin. 20 Several clinical features are typical of PPMS but not of bout-onset MS, including the clinical presentation (progressive myelopathy vs visual loss), the presence of cognitive impairment and genetic factors (see for review, McDonnell and Hawkins 21 ).…”

Section: Progranulin Gene Variability In Ppms C Fenoglio Et Alsupporting

confidence: 73%

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

et al. 2010

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Progranulin (GRN) gene variability has been analyzed in a sample of 354 patients with multiple sclerosis (MS) compared with 343 controls. No significant differences were observed, but by stratifying according to MS subtypes, a significant increased frequency of the rs2879096 TT genotype was found in primary progressive MS (PPMS) patients versus controls (16.0 vs 3.5%, P ¼ 0.023, odds ratio (OR) 5.2, 95% confidence interval (CI) 1.2-21.4). In addition, in PPMS, an association with the C allele of rs4792938 was observed (55.3 vs 33.5%, P ¼ 0.011, OR 2.4, 95% CI 1.2-4.7). An independent population was studied as replication, failing to confirm results previously obtained. Stratifying according to gender, an association with rs4792938 C allele was found in male PPMS patients compared with controls (40.7 vs 26.9%, P ¼ 0.002, OR 1.87, 95% CI 1.2-2.8). An association with the rs2879096T allele was observed (29.2 in patients compared with 18.9% in controls, P ¼ 0.012, OR 1.77, 95% CI 1.1-2.8). Haplotype analysis showed that TC haplotype frequency is increased in PPMS male patients compared with male controls (25.7 vs 16.6%; P ¼ 0.02, OR 1.69, 95% CI 1.1-2.7), whereas the respective GC haplotype seems to exert a protective effect, as its frequency is decreased in patients compared with controls (55.8% vs 70.9%; P ¼ 0.001, OR 0.52, 95% CI 0.4-0.8). Therefore, GRN haplotypes likely influence the risk of developing PPMS in males.

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Section: Progranulin Gene Variability In Ppms C Fenoglio Et Alsupporting

confidence: 73%

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

et al. 2010

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“…CNP protein facilitates oligodendrocyte differentiation and process outgrowth early in the myelination process (45,46), whereas MAG is important in oligodendrocyte-neuron signaling, such that it regulates axon caliber and contributes to axon growth cone collapse, maintaining established axons at the expense of novel growth (24,47,48). The results from Western blotting for CNP and MAG, however, did not reveal developmental changes in myelin-associated protein expression in humans that mirrored the cubic function of the MFLD curve.…”

Section: Discussionmentioning

confidence: 96%

Prolonged myelination in human neocortical evolution

Miller

Duka

Stimpson

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

525

426

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Nerve myelination facilitates saltatory action potential conduction and exhibits spatiotemporal variation during development associated with the acquisition of behavioral and cognitive maturity. Although human cognitive development is unique, it is not known whether the ontogenetic progression of myelination in the human neocortex is evolutionarily exceptional. In this study, we quantified myelinated axon fiber length density and the expression of myelinrelated proteins throughout postnatal life in the somatosensory (areas 3b/3a/1/2), motor (area 4), frontopolar (prefrontal area 10), and visual (areas 17/18) neocortex of chimpanzees (N = 20) and humans (N = 33). Our examination revealed that neocortical myelination is developmentally protracted in humans compared with chimpanzees. In chimpanzees, the density of myelinated axons increased steadily until adult-like levels were achieved at approximately the time of sexual maturity. In contrast, humans displayed slower myelination during childhood, characterized by a delayed period of maturation that extended beyond late adolescence. This comparative research contributes evidence crucial to understanding the evolution of human cognition and behavior, which arises from the unfolding of nervous system development within the context of an enriched cultural environment. Perturbations of normal developmental processes and the decreased expression of myelin-related molecules have been related to psychiatric disorders such as schizophrenia. Thus, these species differences suggest that the human-specific shift in the timing of cortical maturation during adolescence may have implications for vulnerability to certain psychiatric disorders.C omparative studies suggest that human neurobiological development is unique. For example, humans differ from other primates in extending a rapid, fetal-like brain mass growth rate into the first postnatal year, thereby achieving relatively large adult brain size (1). Gene expression patterns related to postnatal development of the prefrontal cortex are delayed in humans compared with chimpanzees and macaque monkeys (2). In addition, synapse maturation (3, 4) and axon myelination (5, 6) occur during later life history stages in humans compared with macaques. Furthermore, recent volumetric data obtained by using in vivo MRI demonstrates that human neural development and aging differ from those of our close nonhuman primate relatives (7-9). Together, these observations indicate that a marked delay in the developmental schedule of human neocortex may play an important role in the growth of connections that contribute to our species-specific cognitive abilities by providing greater opportunities for social learning to influence the establishment of circuits.

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“…It is an open question whether the process of axonal dystrophy is directly caused by the astrocytes through, for example, lack of energy supply or secretion of a toxic factor, or mediated through the impact of astrocytes on oligodendrocytes and their ability to provide metabolic support to axons 34, 35. The effect of astrocytes on axonal density may be related to immaturity of VWM astrocytes, which better promote axonal growth or regeneration than mature astrocytes, while having no differential effect on dendrite growth 36, 37, 38, 39.…”

Section: Discussionmentioning

confidence: 99%

Axonal abnormalities in vanishing white matter

Klok

Bugiani

Vries

et al. 2018

Ann Clin Transl Neurol

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ObjectiveWe aimed to study the occurrence and development of axonal pathology and the influence of astrocytes in vanishing white matter.MethodsAxons and myelin were analyzed using electron microscopy and immunohistochemistry on Eif2b4 and Eif2b5 single‐ and double‐mutant mice and patient brain tissue. In addition, astrocyte‐forebrain co‐culture studies were performed.ResultsIn the corpus callosum of Eif2b5‐mutant mice, myelin sheath thickness, axonal diameter, and G‐ratio developed normally up to 4 months. At 7 months, however, axons had become thinner, while in control mice axonal diameters had increased further. Myelin sheath thickness remained close to normal, resulting in an abnormally low G‐ratio in Eif2b5‐mutant mice. In more severely affected Eif2b4‐Eif2b5 double‐mutants, similar abnormalities were already present at 4 months, while in milder affected Eif2b4 mutants, few abnormalities were observed at 7 months. Additionally, from 2 months onward an increased percentage of thin, unmyelinated axons and increased axonal density were present in Eif2b5‐mutant mice. Co‐cultures showed that Eif2b5 mutant astrocytes induced increased axonal density, also in control forebrain tissue, and that control astrocytes induced normal axonal density, also in mutant forebrain tissue. In vanishing white matter patient brains, axons and myelin sheaths were thinner than normal in moderately and severely affected white matter. In mutant mice and patients, signs of axonal transport defects and cytoskeletal abnormalities were minimal.InterpretationIn vanishing white matter, axons are initially normal and atrophy later. Astrocytes are central in this process. If therapy becomes available, axonal pathology may be prevented with early intervention.

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Myelin-Associated Glycoprotein Is a Myelin Signal that Modulates the Caliber of Myelinated Axons

Cited by 442 publications

References 47 publications

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

Progranulin gene variability increases the risk for primary progressive multiple sclerosis in males

Prolonged myelination in human neocortical evolution

Axonal abnormalities in vanishing white matter

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