Myelin-associated glycoprotein and myelin galactolipids stabilize developing axo-glial interactions

Marcus, Jill R.; Dupree, Jeffrey L.; Popko, Brian

doi:10.1083/jcb.200111047

Cited by 114 publications

(100 citation statements)

References 49 publications

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“…Interestingly, whereas gangliosides are produced most prominently in neurons, production of the gala-series is largely restricted to myelin-producing cells. This finding suggests that the ganglio-and gala-series of glycosphingolipids may play parallel roles in promoting axonal-glial interactions, which is consistent with observations that concomitant deletion of galaseries glycosphingolipids and MAG genes in mice produces a more severe phenotype (34).…”

Section: Discussionsupporting

confidence: 89%

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Yamashita

Wu²,

Sandhoff³

et al. 2005

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

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212

160

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Gangliosides, which are sialylated glycosphingolipids, are the major class of glycoconjugates on neurons and carry the majority of the sialic acid within the central nervous system (CNS). To determine the role of ganglioside synthesis within the CNS, mice carrying null mutations in two critical ganglioside-specific glycosyltransferase genes, Siat9 (encoding GM3 synthase) and Galgt1 (encoding GM2 synthase), were generated. These double-null mice were unable to synthesize gangliosides of the ganglio-series of glycosphingolipids, which are the major ganglioside class in the CNS. Soon after weaning, viable mice developed a severe neurodegenerative disease that resulted in death. Histopathological examination revealed striking vacuolar pathology in the white matter regions of the CNS with axonal degeneration and perturbed axon-glia interactions. These results indicate that ganglioside synthesis is essential for the development of a stable CNS, possibly by means of the promotion of interactions between axon and glia.glycosphingolipid ͉ neurodegeneration ͉ glycosyltransferase

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Section: Discussionsupporting

confidence: 89%

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Yamashita

Wu²,

Sandhoff³

et al. 2005

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

Self Cite

212

160

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“…The prominent paranodal components contactin, NF-155, Caspr, and sulfatide [interacts with versican in vitro (Miura et al, 1999)] seem also not necessary for the selective deposition and binding of versican V2 at the nodes. In CGT-null mice, they are all virtually absent from the severely disturbed terminal glial loops of the paranodes (Poliak et al, 2001;Marcus et al, 2002). Nevertheless, versican V2 and TnR accumulate normally in CGT mutants, as demonstrated by our immunohistochemical analyses.…”

Section: Discussionsupporting

confidence: 68%

Versican V2 Assembles the Extracellular Matrix Surrounding the Nodes of Ranvier in the CNS

Dours-Zimmermann¹,

Maurer²,

Rauch³

et al. 2009

Journal of Neuroscience

105

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The CNS-restricted versican splice-variant V2 is a large chondroitin sulfate proteoglycan incorporated in the extracellular matrix surrounding myelinated fibers and particularly accumulating at nodes of Ranvier. In vitro, it is a potent inhibitor of axonal growth and therefore considered to participate in the reduction of structural plasticity connected to myelination. To study the role of versican V2 during postnatal development, we designed a novel isoform-specific gene inactivation approach circumventing early embryonic lethality of the complete knock-out and preventing compensation by the remaining versican splice variants. These mice are viable and fertile; however, they display major molecular alterations at the nodes of Ranvier. While the clustering of nodal sodium channels and paranodal structures appear in versican V2-deficient mice unaffected, the formation of the extracellular matrix surrounding the nodes is largely impaired. The conjoint loss of tenascin-R and phosphacan from the perinodal matrix provide strong evidence that versican V2, possibly controlled by a nodal receptor, organizes the extracellular matrix assembly in vivo.

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supporting

confidence: 59%

“…It has been shown that NCP1 and CGT mice also have disrupted AGJs in the peripheral nerves (5,19). We have not observed axonal swellings in the sciatic nerves of NCP1 and CGT mutants at the age that we analyzed the animals (P25).…”

Section: Discussionmentioning

confidence: 63%

“…Similar phenotypes were observed at the paranodes in CGT mutants (18,19). CGT encodes an enzyme that is needed for the biosynthesis of two important myelin lipids, galactocerebroside and sulfatide (10,(18)(19)(20)(21). Using subcellular fractionation of NF155 in detergents, Rasband and coworkers (22) proposed a model in which myelin lipids assemble in stable lipid rafts to stabilize the clustering of NF155 at the glial side of AGJs.…”

mentioning

confidence: 68%

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Disruption of axo–glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons

Garcia-Fresco

Sousa

Pillai

et al. 2006

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

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121

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Axo-glial junctions (AGJs) play a critical role in the organization and maintenance of molecular domains in myelinated axons. Neurexin IV͞Caspr1͞paranodin (NCP1) is an important player in the formation of AGJs because it recruits a paranodal complex implicated in the tethering of glial proteins to the axonal membrane and cytoskeleton. Mice deficient in either the axonal protein NCP1 or the glial ceramide galactosyltransferase (CGT) display disruptions in AGJs and severe ataxia. In this article, we correlate these two phenotypes and show that both NCP1 and CGT mutants develop large swellings accompanied by cytoskeletal disorganization and degeneration in the axons of cerebellar Purkinje neurons. We also show that ␣II spectrin is part of the paranodal complex and that, although not properly targeted, this complex is still formed in CGT mutants. Together, these findings establish a physiologically relevant link between AGJs and axonal cytoskeleton and raise the possibility that some neurodegenerative disorders arise from disruption of the AGJs.myelin ͉ paranodes ͉ cerebellum ͉ ataxia T he anatomical organization of myelinated fibers into distinct domains is the basis for the saltatory mode of action potential propagation. In the axons, these molecular domains (internode, juxtaparanode, paranode, and node of Ranvier) form as a result of specific polarization driven by signaling between the myelinating glial cells and neurons that has yet to be fully understood. In the paranodal region, closely apposed axon-glial membranes form specialized cell junctions, which resemble the ladder-like invertebrate septate junctions, and are referred to as paranodal septate junctions or paranodal axo-glial junctions (AGJs) (1-4).Three major proteins have been shown to localize to the paranodal AGJs: NCP1 (also known as Caspr1 or paranodin) and contactin (CNTN) on the axonal side and neurofascin (NF155), the 155-kDa isoform on the glial side (5-9). Although NF155 is the only known glial protein at the paranodal membrane, a number of nonparanodal glial proteins are required for proper formation, maintenance, and distribution of AGJs, as in the case of ceramide galactosyltransferase (CGT), proteolipid protein, myelin-basic protein, myelin-associated glycoprotein, 2Ј,3Ј-cyclic nucleotide 3Ј-phosphodiesterase, and the transcription factor Nkx6-2 (10-17).Genetic ablation of NCP1 and CNTN in mice results in the loss of AGJs and a failure to segregate Na ϩ and K ϩ channels at the nodes and juxtaparanodes, respectively (5, 6). Similar phenotypes were observed at the paranodes in CGT mutants (18,19). CGT encodes an enzyme that is needed for the biosynthesis of two important myelin lipids, galactocerebroside and sulfatide (10,(18)(19)(20)(21). Using subcellular fractionation of NF155 in detergents, Rasband and coworkers (22) proposed a model in which myelin lipids assemble in stable lipid rafts to stabilize the clustering of NF155 at the glial side of AGJs. This model is consistent with the phenotype of CGT mutants in which defective biosynthes...

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Myelin-associated glycoprotein and myelin galactolipids stabilize developing axo-glial interactions

Cited by 114 publications

References 49 publications

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon–glial interactions

Versican V2 Assembles the Extracellular Matrix Surrounding the Nodes of Ranvier in the CNS

Disruption of axo–glial junctions causes cytoskeletal disorganization and degeneration of Purkinje neuron axons

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