NF-M is an essential target for the myelin-directed “outside-in” signaling cascade that mediates radial axonal growth

Garcia, Michael L.; Lobsiger, Christian S.; Shah, Sameer B.; Deerinck, Tom; Crum, John; Young, Darren; Ward, Christopher; Crawford, Thomas O.; Gotow, Takahiro; Uchiyama, Yasuo; Ellisman, Mark H.; Calcutt, Nigel A.; Cleveland, Don W.

doi:10.1083/jcb.200308159

Cited by 152 publications

(196 citation statements)

References 55 publications

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“…We also detected a strong enrichment of phosphorylated neurofilaments in the axonal swellings in NCP1 and CGT mutants. Besides its significance as an indicator of disrupted axonal transport, the phosphorylation of neurofilaments also modulates the interfilament spacing, and it is thought to be part of the signaling for myelin-dependent expansion of axonal caliber in the internodes (45). Although interactions between axons and glia are likely to regulate the axonal caliber, the mechanisms responsible for this regulation are not well understood (4,46).…”

Section: Discussionmentioning

confidence: 99%

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.

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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Section: Discussionmentioning

confidence: 99%

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.

121

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“…In support of this, axons in mutant animals that lack neurofilaments or the NFM tail domain fail to attain their normal caliber (Sakaguchi et al, 1993;Zhu et al, 1997;Garcia et al, 2003;Rao et al, 2003). Conversely, in diseases such as ALS and giant axonal neuropathy, neurofilaments can accumulate excessively, leading to massive balloon-like axonal swellings (Delisle and Carpenter, 1984;Donaghy et al, 1988;Sasaki et al, 1990).…”

Section: Discussionmentioning

confidence: 99%

Neurofilaments Switch between Distinct Mobile and Stationary States during Their Transport along Axons

Trivedi

Jung²,

Brown³

2007

J. Neurosci.

139

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We have developed a novel pulse-escape fluorescence photoactivation technique to investigate the long-term pausing behavior of axonal neurofilaments. Cultured sympathetic neurons expressing a photoactivatable green fluorescent neurofilament fusion protein were illuminated with violet light in a short segment of axon to create a pulse of fluorescent neurofilaments. Neurofilaments departed from the photoactivated regions at rapid velocities, but the overall loss of fluorescence was slow because many of the neurofilaments paused for long periods of time before moving. The frequency of neurofilament departure was more rapid initially and slower at later times, resulting in biphasic decay kinetics. By computational simulation of the kinetics, we show that the neurofilaments switched between two distinct states: a mobile state characterized by intermittent movements and short pauses (average ϭ 30 s) and a stationary state characterized by remarkably long pauses (average ϭ 60 min). On average, the neurofilaments spent 92% of their time in the stationary state. Combining short and long pauses, they paused for 97% of the time, resulting in an average transport rate of 0.5 mm/d. We speculate that the relative proportion of the time that neurofilaments spend in the stationary state may be a principal determinant of their transport rate and distribution along axons, and a potential target of mechanisms that lead to abnormal neurofilament accumulations in disease.

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“…L5 axons were prepared and analyzed as described in ref. 41, with the following modifications. Samples were embedded in Technovit 7100 according to manufacturer's protocol (Heraeus).…”

Section: Methodsmentioning

confidence: 99%

A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration

Chu

Hong²,

Masuda³

et al. 2009

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

214

178

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NF-M is an essential target for the myelin-directed “outside-in” signaling cascade that mediates radial axonal growth

Cited by 152 publications

References 55 publications

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

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

Neurofilaments Switch between Distinct Mobile and Stationary States during Their Transport along Axons

A mouse forward genetics screen identifies LISTERIN as an E3 ubiquitin ligase involved in neurodegeneration

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