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. 2002 Apr;200(4):323–330. doi: 10.1046/j.1469-7580.2002.00038.x

The function of the Periaxin gene during nerve repair in a model of CMT4F *

Anna C Williams 1, Peter J Brophy 1
PMCID: PMC1570694  PMID: 12090399

Abstract

Mutations in the Periaxin (PRX) gene are known to cause autosomal recessive demyelinating Charcot-Marie-Tooth (CMT4F) and Dejerine-Sottas disease. The pathogenesis of these diseases is not fully understood. However, progress is being made by studying both the periaxin-null mouse, a mouse model of the disease, and the protein–protein interactions of periaxin. L-periaxin is a constituent of the dystroglycan–dystrophin-related protein-2 complex linking the Schwann cell cytoskeleton to the extracellular matrix. Although periaxin-null mice myelinate normally, they develop a demyelinating peripheral neuropathy later in life. This suggests that periaxin is required for the stable maintenance of a normal myelin sheath. We carried out sciatic nerve crushes in 6-week-old periaxin-null mice, and, 6 weeks later, found that although the number of myelinated axons had returned to normal, the axon diameters remained smaller than in the contralateral uncrushed nerve. Not only do periaxin-null mice have more hypermyelinated axons than their wild-type counterparts but they also recapitulate this hypermyelination during regeneration. Therefore, periaxin-null mice can undergo peripheral nerve remyelination, but the regulation of peripheral myelin thickness is disrupted.

Keywords: Charcot-Marie-Tooth disease, g-ratio, myelination, nerve crush, peripheral neuropathy

Introduction

Charcot-Marie-Tooth disease is the commonest inherited peripheral neuropathy and affects 1 in 2500 people (Skre, 1974). It generally manifests as a progressive distal muscular atrophy and weakness, with sensory loss in the distal limb extremities. CMT disease was initially divided into two groups: CMT1 or demyelinating neuropathies and CMT2 or axonal neuropathies (Dyck & Lambert, 1968). These groups have been subdivided further on the basis of the gene mutations involved. Autosomal recessive CMT disease (ARCMT) has been called CMT4. To date, eight loci have been implicated in ARCMT disease and four genes identified: early growth response-2 (EGR2) (Warner et al. 1998), myotubularin-related protein-2 (MTMR2) (Bolino et al. 2000), N-myc downstream-regulated gene-1 (NRDG1) (Kalaydjieva et al. 2000) and Periaxin (PRX) (Guilbot et al. 2001; Boerkoel et al. 2001). The pathogenesis of these diseases and the function of the genes involved are not fully understood. The periaxin-null mouse is an excellent mouse model of ARCMT disease and initial studies of the phenotype of this mouse have correlated well with the human version of the disease (Gillespie et al. 2000).

The periaxin gene encodes two proteins with PDZ domains, L-periaxin and S-periaxin, of 147 and 16 kDa, respectively (Dytrych et al. 1998). The PDZ domain is named after the three proteins in which it was first described: postsynaptic density protein-95 (PSD-95), drosophila discs large tumour suppressor gene (dlg) and the tight junction-associated protein ZO-1 (Kornau et al. 1995). The periaxins are expressed in myelinating Schwann cells. During myelination, L-periaxin is predominantly located at the adaxonal membrane, but once myelination is complete, it is localized at the abaxonal membrane (Gillespie et al. 1994), where its PDZ motif is implicated in organizing protein–protein interactions (Sheng, 1996). Periaxin interacts with the dystroglycan–dystrophin-related protein-2 complex linking the Schwann cell cytoskeleton to the extracellular matrix (Sherman et al. 2001). Periaxin-null mice develop an apparently normally myelinated peripheral nervous system, so it appears that the presence of the periaxin proteins is not essential for myelination to occur. However, these mice progress to develop a late onset demyelinating peripheral neuropathy (Gillespie et al. 2000). This suggests that the periaxins are essential for the stabilization of the myelin and to recapitulate myelin sheath development, as the environment in the two conditions is different.

A nerve crush produces axonotmesis (Sunderland second-degree injury) which involves injury to the axon so that Wallerian degeneration occurs distal to the injury. Recovery occurs by axonal sprouting within the intact endoneural tubes of the Schwann cell basal lamina. The regenerated fibres are then remyelinated. Regeneration is directed distally and complete recovery is expected in normal subjects (Sunderland, 1951).

We hypothesized that periaxin is essential for the repair or turnover of myelin sheaths which occurs continually in vivo; hence we carried out sciatic nerve crush on wild-type and periaxin-null mice to determine whether regeneration of the myelin sheath could occur. We assessed myelinated axon number, axon diameter and myelin sheath thickness.

Materials and methods

University of Edinburgh Care of Animals regulations were observed throughout these experiments.

Sciatic nerve crush

Six-week-old mice were anaesthetized with midazolam (3 µg g−1), fentanyl (0.5 µg g−1) and fluanisone (16 µg g−1), and an incision made to expose the right sciatic nerve. At the sciatic notch, the nerve was crushed for 10 s, three times, with jeweller’s forceps. The wound was closed with a clip. After 2 or 6 weeks, the mice were anaesthetized with halothane, and then perfused with 2.5% glutaraldehyde and 2% paraformaldehyde in 0.1 m sodium cacodylate buffer (pH 7.3). The sciatic nerves were removed. The proximal end was cut at the site of crush, at the sciatic notch, or equivalent level on the contralateral leg, and muscle was left on the distal end of the nerve, to allow easy orientation after fixation. The nerves were fixed for 2 h in the same fixative, post-fixed in osmium tetroxide and embedded in Araldite™. Transverse semithin sections of 1 µm were cut immediately distal to the crush site, and stained with Toluidine blue. The myelin thickness of fibres regenerated after crush depends not only on the ability of the Schwann cell to remyelinate but also on the efficiency of axonal sprouting and elongation, and so great care was taken to perform measurements at the same distance from the crush site.

The total cross-sectional area of nerve was measured using the IP Laboratory Spectrum software. Measurements of myelinated axon number, density, diameter and myelin thickness were then performed on 30% of the area of each nerve chosen randomly, using the IP Laboratory Spectrum software. Random areas of the nerve were selected by superimposing a numbered grid and using a random number table to select squares. Analysis of significance was carried out using the t-test for normally distributed data and the Kolmogorov–Smirnov test for non-parametric data. Regression lines were compared using anova. Each experimental group consisted of between three and five mice.

Results

Nerve crushes were performed on the sciatic nerves of wild-type and periaxin-null mice at 6 weeks of age when myelination is thought to be complete and there is little sign of peripheral nerve pathology in the periaxin-null mice. This was to ensure that any demyelination and remyelination was due to nerve crush and recovery rather than disease. Analysis of regeneration was carried out at 2 and 6 weeks after crush (8 and 12 weeks of age). On each occasion the uncrushed, contralateral sciatic nerve was taken as an internal control. We examined the nerves 4 days after crush to ensure that the crush technique was efficient at causing demyelination (secondary to axonotmesis) and found that the efficiency of our crush technique is adequate to affect most myelinated axons. Hence we can confidently attribute the presence of myelin 2 weeks after crush to remyelination.

Myelinated axon number

We counted the number of myelinated axons to determine if periaxin-null mice and wild-type mice have equivalent baseline numbers of myelinated axons, and if, after crush, the nerves could regenerate the normal number of myelinated axons. It is known that in human demyelinating CMT disease, axonal loss contributes much to the symptoms of the disease (Krajewski et al. 2000), so we wanted to determine whether axonal loss was increased after experimental nerve crush in periaxin-null mice.

At baseline, in uncrushed nerves, periaxin-null and wild-type mice have an equivalent number of myelinated axons. At 2 weeks after crush, the number of myelinated axons in both wild-type and periaxin-null mice is back to normal, suggesting that recovery of the number of myelinated axons is complete by 2 weeks after crush (Fig. 1).

Fig. 1.

Fig. 1

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Myelinated axon number in periaxin-null mice is normal at baseline (uncrushed) or 2 and 6 weeks after sciatic nerve crush (crushed). Values shown are means ± SEM for 3–5 experimental mice.

Cross-sectional area of nerve

It has been reported previously that the cross-sectional area of nerves increases in animal models of demyelinating CMT disease (Sahenk, 1999). The average cross-sectional area of a periaxin-null mouse sciatic nerve is significantly larger than that of the wild-type (unpaired t-test P < 0.001). As Fig. 1 shows, the number of myelinated fibres is equivalent, so the density of axons in periaxin-null mice is markedly reduced (unpaired t-test P < 0.001) (Fig. 2). There is no change in density with age over this period.

Fig. 2.

Fig. 2

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The cross-sectional area of periaxin-null sciatic nerve is significantly larger than that of the wild-type. The density of myelinated axons is significantly reduced in periaxin-null sciatic nerve. Values shown are means ± SEM for 19 wild-type and 23 periaxin-null mice. Asterisks indicate statistically significant differences (P > 0.001, unpaired t-test).

The reduced density of fibres (Fig. 3), and the increase in total area of the nerve in periaxin-null mice, appears to be due to an increase in ECM (Fig. 3). The clinical correlate of this observation suggests that this difference is real and not an artefact of the tissue processing. At higher power, this is confirmed, as empty space is not apparent (data not shown).

Fig. 3.

Fig. 3

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Light micrographs of wild-type (left) and periaxin-null (right) uncrushed sciatic nerve at 12 weeks of age show the reduced density of myelinated axons and increased extracellular matrix in the periaxin-null mice. Scale bar = 10 μm.

Frequency distribution of axon diameters in the nerve

Myelination of an axon causes phosphorylation of neurofilaments, which is believed to increase the axon diameter. Therefore, in causing demyelination, nerve crush reduces neurofilament phosphorylation, which leads to more densely packed neurofilaments and a smaller axon diameter (de Waegh et al. 1992). We determined if there were baseline differences in the frequency distribution of axon diameters between periaxin-null and wild-type mice, and whether this changed after crush.

The frequency distribution of axon diameters in wild-type or periaxin-null mouse sciatic nerve does not fit a normal distribution, but is skewed to the left indicating a higher representation of smaller myelinated axons (Fig. 4).

Fig. 4.

Fig. 4

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Axon diameter frequency distribution in sciatic nerve from wild-type and periaxin-null mice in uncrushed nerves, and 2 and 6 weeks after crush, respectively. The percentage frequency is plotted against axon diameter (μm). Uncrushed periaxin-null nerves have a higher percentage of small diameter fibres. After crush, the proportion of smal diameter axons increases in both wild-type and periaxin-null nerves and although this reverts slowly towards normal, at 6 week there are still more smaller axons. Values shown are means ± SEM of an average of 957 axons per each of 3–5 sciatic nerves for ea h group.

In uncrushed nerves, the axon diameter size distribution does not change with time between 8 and 12 weeks of age. Periaxin-null nerves have a higher proportion of smaller axon diameters compared to wild-type nerves, both in the crushed and in the uncrushed situations (Kolmogorov–Smirnov test P < 0.001).

Nerve crush, in both wild-type and periaxin-null mice, shifts the curve further to the left, indicating an increase in the proportion of smaller diameter myelinated axons. The difference is not fully resolved by 6 weeks after crush, indicating that the axon diameters have still not returned to their previous size, even in wild-type mice (Kolmogorov–Smirnov test P < 0.001).

Myelin thickness

We determined whether the thickness of myelin is different between periaxin-null and wild-type nerves at baseline and after crush. The g-ratio is a measure of the thickness of the myelin sheath around an axon, compared to its diameter, and is derived by dividing the axon diameter by the fibre diameter. Therefore, as the myelin thickness increases, the g-ratio decreases and vice versa. If there is no myelin sheath, then the g-ratio is 1.

The g-ratio is plotted against the axon diameter to compare directly the amount of myelin around a fixed sized axon. Figure 5 shows regression lines for the average g-ratio values for each axon diameter range from all nerves tested in each experimental group. The regression lines for the crushed and uncrushed wild-type nerves are superimposed at both 2 weeks and 6 weeks after crush, indicating repair of the myelin sheath to normal by 2 weeks. However, in periaxin-null mice, the crushed nerve regression line is significantly higher than the uncrushed line at 2 weeks after crush (P = 0.007). The difference is less marked, but still present, at 6 weeks after crush (P = 0.002). Thus, crushed nerves have thinner myelin sheaths compared to uncrushed nerves in the periaxin-null mouse. However, on comparing these regression lines to wild-type mice, uncrushed periaxin-null nerves show a lower g-ratio than the corresponding wild-type nerves (P = 0.02 at 2 weeks, P = 0.01 at 6 weeks), indicating hypermyelination, especially of smaller diameter fibres. The two regression lines for crushed periaxin-null and wild-type nerves are very similar 2 weeks after crush, indicating that there had been repair of the myelin sheath at the same rate after demyelination. At 6 weeks after crush these diverge as the periaxin-null nerve g-ratios decrease, thus indicating hypermyelination. Therefore, crushed periaxin-null nerves become more hypermyelinated and more abnormal with time.

Fig. 5.

Fig. 5

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Graphs of the mean g-ratio plotted against axon diameter for wild-type and periaxin-null mice at 2 and 6 weeks after crush. The axon diameter values are grouped according to size, and the mean g-ratio is plotted for each size range. For ease of comparison, the mean g-ratio is plotted against the natural log of the axon diameter, giving a straight regression line. The equations for the regression lines are displayed. Mean g-ratios are for from an average of 957 axons for each of 3–5 sciatic nerves in each experimental group. The mean g-ratio values for the crushed and uncrushed wild-type mice are superimposed at both 2 and 6 weeks after nerve crush and show that remyelination is carried out to completeness by 2 weeks after crush. The mean g-ratio values for the uncrushed periaxin-null nerves are lower than their wild-type equivalents, indicating hypermyelination. After nerve crush, the periaxin-null axon g-ratios are very similar to their wild-type counterparts at 2 weeks, indicating a similar initial rate of remyelination. However, at 6 weeks after crush, the g-ratio values have decreased, indicating progressive hypermyelination, moving closer to the hypermyelinated state of the uncrushed nerves.

This is shown in a different way in Fig. 6, which shows the results of g-ratios for a single experimental mouse at each time point. In the wild-type mice, the g-ratio values from crushed and uncrushed nerves are indistinguishable at 2 and 6 weeks after crush, suggesting that myelin thickness returns to normal within 2 weeks. In the periaxin-null mice, the g-ratio values are lower in the uncrushed nerve compared to the crushed nerve at 2 weeks, though the difference is less at 6 weeks after crush when the g-ratio values are lower, indicating hypermyelination.

Fig. 6.

Fig. 6

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Graphs of the g-ratio for each axon measured in crushed and uncrushed nerve, plotted against its axon diameter, for one experimental animal for each group. This emphasizes that there is no difference in g-ratio values for crushed and uncrushed wildtype axons at 2 or 6 weeks after crush, indicating complete remyelination. However, there are distinct populations of g-ratio values from crushed and uncrushed periaxin-null axons, at 2 weeks after crush. The uncrushed values are lower, indicating hypermyelination, and the crushed values are similar to that of crushed wild-type axons at this timepoint. At 6 weeks after crush, the crushed and uncrushed periaxin-null axon g-ratio values are more similar, and lower, indicating progressive hypermyelination.

Discussion

Nerve crush is a commonly used experimental model in rodents to allow investigations of peripheral nerve injury and regeneration. This has been evaluated and standardized by several groups (Bridge et al. 1994; Nawwar et al. 1995). The failure of patients with demyelinating CMT disease to remyelinate normally or fully is still not understood. Hence there is value in studying this issue in good mouse models of the disease.

There are now several mouse models of human CMT disease (reviewed in Young & Suter, 2001), and the periaxin-null mouse is a model of an autosomal recessive type. Hence, these mice provide an excellent opportunity to study the pathophysiology of disease.

Baseline differences between periaxin-null and wild-type mice

We have shown that there is no difference in the number of myelinated axons in wild-type and periaxin-null sciatic nerves up to 12 weeks of age. Thus, periaxin-null mice have the capacity to form normal numbers of myelinated axons. It is known that peripheral nerve development involves bidirectional axon–glial interactions (de Waegh et al. 1992) suggesting that periaxin is not critical in this signalling at least at early stages. In human demyelinating CMT disease it is thought that most symptoms occur when axons are lost, secondary to demyelination, although myelin abnormalities can be seen earlier on electrophysiological testing (Krajewski et al. 2000). Indeed, at 9 months of age, periaxin-null mice also show a reduction in myelinated axons (Sherman et al. unpublished).

However, even at this early age, prior to axonal loss, there is a higher proportion of smaller diameter axons in periaxin-null nerves. Shiverer and Trembler mice, which have disordered myelination due to myelin basic protein and peripheral myelin protein-22 mutations, respectively, also show this (Kirkpatrick et al. 2001; de Waegh et al. 1992). This may be secondary to the presence of thin myelin around some axons, as it is postulated that the myelin sheath signals to the axon, causing an increase in the number of neurofilaments and state of neurofilament phosphorylation both of which increase axon calibre (Kriz et al. 2000). However, many of the axons in the periaxin-null mouse are hypermyelinated, as shown in Fig. 5. It is known that the rate of slow axonal transport is reduced in Trembler and Shiverer mouse peripheral nerve, where axon diameters are small (de Waegh et al. 1992; Kirkpatrick et al. 2001), and so it may be that these axo-glial units are less stable over time. Therefore, there appears to be disordered axo–glial interactions in periaxin-null mice even at this early age.

Extracellular matrix

Periaxin-null sciatic nerves are larger in total cross-sectional area than wild-type nerves, due to an increase in ECM. In some patients with demyelinating CMT disease, peripheral nerves are visible or palpable (Harding & Thomas, 1980). This is thought to be due to a combination of an increase in ECM and the presence of onion-bulb structures around remyelinated axons. The dystroglycan–dystrophin-related protein-2 complex links the Schwann cell cytoskeleton to the extracellular matrix, and it may provide a signalling link as well as a physical one. The absence of periaxin may alter this signalling affecting both the Schwann cell and the ECM.

Differences between periaxin-null and wild-type mice after nerve crush

After crush, the number of myelinated axons in wild-type and periaxin-null sciatic nerve returns to normal within 2 weeks. However, the axon diameters decrease in both wild-type and periaxin-null mice, and do not fully recover to normal even after 6 weeks. Similarly, Bridge et al. (1994) found that 8 weeks after nerve crush in wild-type rats, axon size had also not returned to normal, yet electrophysiological and behavioural testing results were normal.

Crushed wild-type axons repair their myelin sheath to normal by 2 weeks after crush. Crushed periaxin-null axons initially remyelinate at the same rate as wild-type crushed axons by 2 weeks after crush, but then become hypermyelinated.

Thus, periaxin-null mice can remyelinate regenerated fibres after nerve crush. Interestingly, periaxin-null nerves have very similar measurements of myelin thickness to wild-type nerves, shortly after crush, but later, hypermyelination occurs. This suggests that although these axons can remyelinate, the mechanisms that regulate myelin thickness are deranged, so abnormally thick myelin sheaths occur. Thus, periaxin may be involved in the regulation of myelin sheath thickness, and it may be that this hypermyelination later leads to the progressive demyelination and dysfunction seen both in the mouse model and in human CMT patients.

At this early age, in this strain background, the periaxin-null mouse has little pathology and a mild phenotype, but by 6 months of age the mice are severely affected (Gillespie et al. 2000). The human form of the disease seems more variable with both severe phenotypes (Boerkoel et al. 2001; Takashima et al. 2002) (Dejerine-Sottas disease) and milder forms described (Guilbot et al. 2001; Takashima et al. 2002). This may partly reflect the different genetic backgrounds on which the Prx mutations are superimposed.

Acknowledgments

We wish to thank Steven Mitchell and Mary Davie for technical help, the University of Edinburgh for a fellowship for ACW, and the Wellcome Trust for financial support.

References

  1. Boerkoel CF, Takashima H, Stankiewicz P, Garcia CA, Leber SM, Rhee-Morris L, et al. Periaxin mutations cause recessive Dejerine-Sottas neuropathy. Am. J. Hum. Genet. 2001;68:325–333. doi: 10.1086/318208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bolino A, Muglia M, Conforti FL, LeGuern E, Salih MA, Georgiou DM, et al. Charcot-Marie-Tooth type 4B is caused by mutations in the gene encoding myotubularin-related protein-2. Nat. Genet. 2000;25:17–19. doi: 10.1038/75542. [DOI] [PubMed] [Google Scholar]
  3. Bridge PM, Ball DJ, Mackinnon SE, Nakao Y, Brandt K, Hunter DA, et al. Nerve crush injuries – a model for axonotmesis. Exp. Neurol. 1994;127:284–290. doi: 10.1006/exnr.1994.1104. [DOI] [PubMed] [Google Scholar]
  4. Dyck PJ, Lambert EH. Lower motor and primary sensory neuron diseases with peroneal muscular atrophy. I. Neurologic, genetic, and electrophysiologic findings in hereditary polyneuropathies. Arch. Neurol. 1968;18:603–618. doi: 10.1001/archneur.1968.00470360025002. [DOI] [PubMed] [Google Scholar]
  5. Dytrych L, Sherman DL, Gillespie CS, Brophy PJ. Two PDZ domain proteins encoded by the murine periaxin gene are the result of alternative intron retention and are differentially targeted in Schwann cells. J. Biol. Chem. 1998;273:5794–5800. doi: 10.1074/jbc.273.10.5794. [DOI] [PubMed] [Google Scholar]
  6. Gillespie CS, Sherman DL, Blair GE, Brophy PJ. Periaxin, a novel protein of myelinating Schwann cells with a possible role in axonal ensheathment. Neuron. 1994;12:497–508. doi: 10.1016/0896-6273(94)90208-9. [DOI] [PubMed] [Google Scholar]
  7. Gillespie CS, Sherman DL, Fleetwood-Walker SM, Cottrell DF, Tait S, Garry EM, et al. Peripheral demyelination and neuropathic pain behavior in periaxin-deficient mice. Neuron. 2000;26:523–531. doi: 10.1016/s0896-6273(00)81184-8. [DOI] [PubMed] [Google Scholar]
  8. Guilbot A, Williams A, Ravise N, Verny C, Brice A, Sherman DL, et al. A mutation in periaxin is responsible for CMT4F, an autosomal recessive form of Charcot-Marie-Tooth disease. Hum. Mol. Genet. 2001;10:415–421. doi: 10.1093/hmg/10.4.415. [DOI] [PubMed] [Google Scholar]
  9. Harding AE, Thomas PK. The clinical features of hereditary motor and sensory neuropathy types I and II. Brain. 1980;103:259–280. doi: 10.1093/brain/103.2.259. [DOI] [PubMed] [Google Scholar]
  10. Kalaydjieva L, Gresham D, Gooding R, Heather L, Baas F, de Jonge R, et al. N-myc downstream-regulated gene 1 is mutated in hereditary motor and sensory neuropathy-Lom. Am. J. Hum. Genet. 2000;67:47–58. doi: 10.1086/302978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Kirkpatrick LL, Witt AS, Payne HR, Shine HD, Brady ST. Changes in microtubule stability and density in myelin-deficient shiverer mouse CNS axons. J. Neurosci. 2001;21:2288–2297. doi: 10.1523/JNEUROSCI.21-07-02288.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Kornau HC, Schenker LT, Kennedy MB, Seeburg PH. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science. 1995;269:1737–1740. doi: 10.1126/science.7569905. [DOI] [PubMed] [Google Scholar]
  13. Krajewski KM, Lewis RA, Fuerst DR, Turansky C, Hinderer SR, Garbern J, et al. Neurological dysfunction and axonal degeneration in Charcot-Marie-Tooth disease type 1A. Brain. 2000;123:1516–1527. doi: 10.1093/brain/123.7.1516. [DOI] [PubMed] [Google Scholar]
  14. Kriz J, Zhu Q, Julien JP, Padjen AL. Electrophysiological properties of axons in mice lacking neurofilament subunit genes: disparity between conduction velocity and axon diameter in absence of NF-H. Brain Res. 2000;885:32–44. doi: 10.1016/s0006-8993(00)02899-7. [DOI] [PubMed] [Google Scholar]
  15. Nawwar AM, Sherif MF, Barakat NG. Instrumented forceps for measurement of nerve compression forces. J. Biomech. Eng. 1995;117:53–58. doi: 10.1115/1.2792270. [DOI] [PubMed] [Google Scholar]
  16. Sahenk Z. Abnormal Schwann cell–axon interactions in CMT neuropathies. The effects of mutant Schwann cells on the axonal cytoskeleton and regeneration-associated myelination. Ann. N.Y. Acad. Sci. 1999;883:415–426. [PubMed] [Google Scholar]
  17. Sheng M. PDZs and receptor/channel clustering: rounding up the latest suspects. Neuron. 1996;17:575–578. doi: 10.1016/s0896-6273(00)80190-7. [DOI] [PubMed] [Google Scholar]
  18. Sherman DL, Fabrizi C, Gillespie CS, Brophy PJ. Specific disruption of a schwann cell dystrophin-related protein complex in a demyelinating neuropathy. Neuron. 2001;30:677–687. doi: 10.1016/s0896-6273(01)00327-0. [DOI] [PubMed] [Google Scholar]
  19. Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin. Genet. 1974;6:98–118. doi: 10.1111/j.1399-0004.1974.tb00638.x. [DOI] [PubMed] [Google Scholar]
  20. Sunderland S. Classification of peripheral nerve injuries producing loss of function. Brain. 1951;74:491. doi: 10.1093/brain/74.4.491. [DOI] [PubMed] [Google Scholar]
  21. Takashima H, Boerkoel CF, De Jonghe P, Ceuterick C, Martin J-J, Voit T, Schroder J-M, Williams A, Brophy PJ, Timmerman V, Lupski JR. Periaxin mutations cause a broad spectrum of demyelinating neuropathies. Ann. Neurol. 2002 doi: 10.1002/ana.10213. in press. [DOI] [PubMed] [Google Scholar]
  22. de Waegh SM, Lee VM, Brady ST. Local modulation of neurofilament phosphorylation, axonal caliber, and slow axonal transport by myelinating Schwann cells. Cell. 1992;68:451–463. doi: 10.1016/0092-8674(92)90183-d. [DOI] [PubMed] [Google Scholar]
  23. Warner LE, Mancias P, Butler IJ, McDonald CM, Keppen L, Koob KG, et al. Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies. Nat. Genet. 1998;18:382–384. doi: 10.1038/ng0498-382. [DOI] [PubMed] [Google Scholar]
  24. Young P, Suter U. Disease mechanisms and potential therapeutic strategies in Charcot-Marie-Tooth disease. Brain Res. Brain Res. Rev. 2001;36:213–221. doi: 10.1016/s0165-0173(01)00097-2. [DOI] [PubMed] [Google Scholar]

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