Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination

Lappe-Siefke, Corinna; Goebbels, Sandra; Gravel, Michel; Nicksch, Eva; Lee, John; Braun, Peter E.; Griffiths, I. R.; Nave, Klaus‐Armin

doi:10.1038/ng1095

Cited by 926 publications

(1,037 citation statements)

References 41 publications

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“…To obtain an oligodendrocyte-specific Nogo-A KO mouse line, mice expressing Cre-recombinase under the control of the 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase (Cnp-Cre þ / À ) 30 were crossed with mice in which exon 3 of the Rtn4 gene was flanked by loxP sites (Rtn4 flox/flox ) ( Figure 1a). CNPase is a well-characterized component and marker for myelin and oligodendrocytes.…”

Section: Resultsmentioning

confidence: 99%

“…The Cnp-Cre line was generated in the laboratory of Klaus-Armin Nave. 30 The Thy1-Cre line was obtained from the Jackson Laboratory (Bar Harbor, ME, USA) (FVB/N-Tg(Thy1-cre)1Vln/J) and back-crossed with C57BL/6 background more than eight times before the breeding was started with Rtn4 flox/flox animals. All procedures and surgeries were performed on 2-4 month old mice of mixed genders and different genotypes.…”

Section: Moreover Inflammation-inducing Agents Such As Zymosan or Pamentioning

confidence: 99%

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Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

et al. 2014

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Nogo-A is a well-known myelin-enriched inhibitory protein for axonal growth and regeneration in the central nervous system (CNS). Besides oligodendrocytes, our previous data revealed that Nogo-A is also expressed in subpopulations of neurons including retinal ganglion cells, in which it can have a positive role in the neuronal growth response after injury, through an unclear mechanism. In the present study, we analyzed the opposite roles of glial versus neuronal Nogo-A in the injured visual system. To this aim, we created oligodendrocyte (Cnp-Cre þ / À xRtn4/Nogo-A flox/flox ) and neuron-specific (Thy1-Cre tg þ xRtn4 flox/flox ) conditional Nogo-A knock-out (KO) mouse lines. Following complete intraorbital optic nerve crush, both spontaneous and inflammation-mediated axonal outgrowth was increased in the optic nerves of the glia-specific Nogo-A KO mice. In contrast, neuron-specific deletion of Nogo-A in a KO mouse line or after acute gene recombination in retinal ganglion cells mediated by adeno-associated virus serotype 2.Cre virus injection in Rtn4 flox/flox animals decreased axon sprouting in the injured optic nerve. These results therefore show that selective ablation of Nogo-A in oligodendrocytes and myelin in the optic nerve is more effective at enhancing regrowth of injured axons than what has previously been observed in conventional, complete Nogo-A KO mice. Our data also suggest that neuronal Nogo-A in retinal ganglion cells could participate in enhancing axonal sprouting, possibly by cis-interaction with Nogo receptors at the cell membrane that may counteract trans-Nogo-A signaling. We propose that inactivating Nogo-A in glia while preserving neuronal Nogo-A expression may be a successful strategy to promote axonal regeneration in the CNS.

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Section: Resultsmentioning

confidence: 99%

Section: Moreover Inflammation-inducing Agents Such As Zymosan or Pamentioning

confidence: 99%

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

et al. 2014

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“…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 ). Given these particular features, Trapp and Nave 17 hypothesized that, if relapses are secondary in MS pathogenesis, the progression of permanent neurological disability in patients supports a primary, age-related neurodegenerative process similar to that occurring in Alzheimer's disease, and its variants.…”

Section: Progranulin Gene Variability In Ppms C Fenoglio Et Almentioning

confidence: 99%

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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“…Long-term interactions between axons and their myelin sheaths are poorly understood, but transgenic mice show signs of axonal degeneration in the absence of the myelin protein proteolipid protein (PLP), the enzyme 2 0 ,3 0 -cyclic nucleotide 3 0 -phosphodiesterase (CNP), or the connexins (Cx) 32 and 47, gap-junction channel-forming proteins expressed specifically by oligodendrocytes. [20][21][22] Oligodendrocytes also induce Na þ Ch clustering along retinal ganglion cell axons via secreted factors and cell contact. [23][24][25] The clustering of Na þ Ch at developing nodes of Ranvier in the optic nerve is mediated via interactions between oligodendroglial neurofascin and axonal paranodin/Caspr-contactin complex at the myelin attachment zone.…”

Section: Oligodendrocytes Are Essential For Axon Functionmentioning

confidence: 99%

Functions of optic nerve glia: axoglial signalling in physiology and pathology

Butt

Pugh

Hubbard

et al. 2004

Eye

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An early concept of glial function envisaged them as passive and unexcitable structural elements, much like the connective tissues of organs in the periphery. It is now known that glia have a widespread range of physiological roles and react to all forms of pathological insult. This paper reviews the major functions of oligodendrocytes and astrocytes, the main types of glia in the optic nerve, and examines novel NG2-glia, otherwise known as oligodendrocyte progenitor cells (OPCs). The major function of oligodendrocytes is to produce the myelin sheaths that insulate CNS axons, but they also have important roles in the establishment of nodes of Ranvier, the sites of action potential propagation, and axonal integrity. Astrocytes have multiple physiological and pathological functions, including potassium homeostasis and metabolism, and reactive astrogliosis in response to CNS insults. The bulk of NG2-glia are postmitotic complex cells, distinct from OPCs, and respond to any insult to the CNS by a rapid and stereotypic injury response. This may be their primary unction, but NG2-glia, or a subpopulation of NG2-expressing adult OPCs, also provide remyelinating oligodendrocytes following demyelination. Oligodendrocytes, astrocytes, and NG2-glia all contact axons at nodes of Ranvier and respond to glutamate, ATP, and potassium released during axonal electrical activity. Glutamate and ATP evoke calcium signalling in optic nerve glia and have dual roles in physiology and pathology, coupling glial functions to axonal activity during normal activity, but enhanced activation induces an injury response, as seen following injury, demyelination, and ischaemia.

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Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination

Cited by 926 publications

References 41 publications

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

Cell type-specific Nogo-A gene ablation promotes axonal regeneration in the injured adult optic nerve

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

Functions of optic nerve glia: axoglial signalling in physiology and pathology

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