Brain, Vol. 125, No. 10, 2213-2221,
October 2002
© 2002 Oxford University Press
PMP22 overexpression causes dysmyelination in mice
1 INSERM U491, Medical Genetics and Development, 2 UPRES JE 2053, Nervous and Muscular Biopathology, 3 Service de Microscopie Électronique, Faculté de Médecine de la Timone, 4 Movement, Development and Pathology Laboratory, CNRS 31, Chemin J. Aiguier, Marseille, France*These two authors contributed equally to this work
Correspondence to: M. Fontés, INSERM U491, Medical Genetics and Development, Faculté de Médecine de la Timone, 27 Boulevard J. Moulin, 13385 Marseille cedex 5, France E-mail: fontes{at}medecine.univ-mrs.fr
Received February 27, 2002. Revised June 12, 2002. Accepted June 16, 2002.
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Charcot–Marie–Tooth (CMT) disease is the most frequent hereditary peripheral neuropathy in humans. Its prevalence is about one in 2500. A subform, CMT1A, is transmitted as an autosomal dominant trait. An estimated 75% of patients are affected. This disorder has been shown to be associated with the duplication of a 1.5 Mb region of the short arm of chromosome 17, in which the PMP22 gene has been mapped. We have constructed a murine model of CMT1A by inserting into the murine genome a human YAC containing peripheral myelin protein 22 (PMP22) and its flanking controlling elements. We describe the behaviour of the C22 line (seven copies of YAC, 2.1 times PMP22 overexpression) during the myelination process. Electron microscopy, morphometry, electrophysiology, nerve conduction and expression of specific markers (e.g. Krox20) in normal and pathological Schwann cells demonstrated that PMP22 overexpression leads to a defect in the myelination of axons. The largest axons are the most affected. Only a few demyelination/remyelination processes were observed. Moreover, PMP22 overexpression probably enhances collagen synthesis by fibroblasts, before myelination, demonstrating that structures other than Schwann cells are affected by PMP22 overexpression. Classically, CMT1A was thought to be induced by a demyelination process following a phase of normal myelination, yet our data suggest that dysmyelination should be considered as a major factor for the disease.
Keywords: axon; Charcot–Marie–Tooth; collagen; myelin; PMP22
Abbreviations: CMT = Charcot–Marie–Tooth disease; MBP = myelin basic protein; P = post-natal stage; PMP22 = peripheral myelin protein 22
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Introduction |
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TopSummaryIntroductionMaterial and methodsResultsDiscussionReferences |
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Charcot–Marie–Tooth disease (CMT) is the most frequent hereditary peripheral neuropathy in humans. Its prevalence is about one in 2500. An estimated 75% of patients are affected by a subform, CMT1A, transmitted as an autosomal dominant trait (Skre, 1974
).
This disorder is associated with the duplication of a 1.5 Mb region on the short arm of chromosome 17 (Lupski et al., 1991; Raeymaekers et al., 1991). In CMT1A patients the human homologue peripheral myelin protein (PMP22) of the murine pmp22 gene has been mapped by several groups in the duplicated region (Matsunami et al., 1992; Patel et al., 1992; Timmerman et al., 1992; Valentijn et al., 1992). The role of PMP22 in the CMT1A phenotype has been strengthened by the observation of rare point mutations in the gene of patients not carrying the duplication. In addition, deletion of the region including the PMP22 gene is associated with a different peripheral neuropathy known as hereditary neuropathy with liability to pressure palsies (Chance et al., 1993).
Clinically, CMT1A is characterized by progressive weakness and atrophy of the distal muscles of the limbs, which generally appear in the second or third decade of life (Dyck et al., 1968). This disorder is also associated with drastically decreased nerve conduction velocity of both motor and sensory fibres. Histologically, CMT1A is characterized by a loss of nerve fibres and numerous segmental demyelinations associated with proliferation of Schwann cells, leading to characteristic onion bulb formations around the demyelinated or partially remyelinated axons. These histological observations have led authors to propose that CMT1A disease was due to a demyelination–remyelination process. In most cases, nerve conduction velocity seems to be affected very early, and no further reduction is observed with aging (Killian et al., 1996; Berciano et al., 2000). Because a detailed chronology of the defects in the myelination process cannot be obtained in humans, it is unknown which mechanisms lead to the CMT1A phenotype, especially during the asymptomatic steps. It is necessary to gain more data to develop a therapy for reversing the disorders in adults.
We formerly constructed a murine model of CMT1A by overexpressing the human PMP22 gene in a murine background. In the murine oocytes we injected a human YAC, containing PMP22 and its flanking control elements. The five transgenic lines obtained exhibited an autosomal dominant peripheral neuropathy, with different degrees of severity (Huxley et al., 1996, 1998; Norreel et al., 2001). The severity of the neuropathy is clearly associated with increased transgene expression, correlated with the number of YAC copies. This observation agrees with the dosage-sensitive nature of the PMP22 gene (Lupski et al., 1992). Moreover, breeding the different lines to homozygosity led to the appearance of the neuropathy in lines with two out of four of integrated YACs, demonstrating that variations in the phenotype did not depend on the genetic background.
Other rodent models of PMP22 overexpression have been generated by other groups (Magyar et al., 1996; Sereda et al., 1996; Perea et al., 2001). They suggested that the myelination process itself could be impaired by PMP22 overexpression, although no systematic chronological observation of the early myelinating stages has been performed.
These data raise the following question: does the initial PMP22 overexpression lead to a demyelinating or to a dysmyelinating phenomenon? In other words, does PMP22 overexpression affect the myelination process itself? In order to answer this, we performed a chronological study of the myelin formation in normal as well as in transgenic animals from birth to the end of the second post-natal week, using the previously described C22 line (seven YAC copies; Huxley et al., 1996). The histological study was completed by an immunological study of the expression of several markers in normal and pathological Schwann cells. The results demonstrate that PMP22 overexpression leads to an imperfect myelination of axons, in particular of the largest ones. Only few demyelination–remyelination processes were seen. Moreover, before myelination, PMP22 overexpression enhanced the synthesis of collagen by fibroblasts, showing that Schwann cells are not the only structure affected by PMP22 overexpression.
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Histology and morphometry
Sciatic nerves were dissected out from transgenic and control mice at four post-natal (P) stages (in days): P0 (defined as the first 24 h after birth), P3, P7 and P16. Nerves were fixed in 4% paraformaldehyde and 2.5% glutaraldehyde (in 0.2 M phosphate buffer, pH 7.4) for 1.5 h, rinsed for 1 h in 0.1 M glycine in water, and then post-fixed in 2% osmium tetroxide-potassium ferrocyanide for 2 h. After a rinse in veronal acetate buffer (0.05 M, pH 7.4), the tissue was stained with 1% uranyl acetate in the same buffer for 3 h. Dehydration was performed in acetone and the samples were embedded in Epon (Massacrier et al., 1990
). Semi-thin (2 µm) sections were cut perpendicularly to the axis of the nerves and mounted. Some were also stained using toluidine blue. Unstained sections were visualized using a Sony TV camera connected to a Zeiss microscope. Digitized pictures were obtained from unstained slides by a Perceptics Pipeline card fitted into a Macintosh Mac II Ci computer and controlled by the NIH ‘Image’ program (version 1.4). The circle equivalent diameter of axons and the thickness of the myelin sheath were deduced from the cross-sectional area of axoplasms and of the whole myelinated fibres. The same data were also used to estimate the cross-sectional areas occupied by myelinated axons.
Ultrathin transverse sections of sciatic nerves were stained using lead citrate and then observed under a Jeol 1200 CX electron microscope.
Immunocytochemical study
Sciatic nerves were fixed in 4% paraformaldehyde in phosphate buffer (0.1 M, pH 7.4) for 1 h, and then rinsed in the same buffer. They were cryoprotected in the same buffer containing increasing amounts of sucrose (5 and 10% for 1 h, 15% overnight), and then frozen in liquid nitrogen vapour and stored at –80°C. Transverse sections (12 µm) of the nerve were cut using a Microm cryostat and collected onto gelatinized slides.
Slides were rinsed in phosphate buffer, dehydrated in absolute ethanol, and then rehydrated in phosphate buffer. Aldehyde groups were blocked for 20 min in phosphate buffer containing 0.1 M glycine. Slides were preincubated in phosphate buffer containing normal goat serum (NGS; 10%) and Triton X-100 (0.1%). Incubation with primary antibody was performed overnight at 4°C. After a short rinse in phosphate buffer containing 5% NGS and Triton X-100 (0.1%), slides were incubated in anti-rabbit immunoglobulin G (IgG) coupled to horse radish peroxidase (Amersham) for 2 h at room temperature. Slides were rinsed in the same buffer and then in Tris–HCl (0.05 M, pH 7.45). They were incubated in diaminobenzidine (DAB; 0.3 mg/ml in Tris–HCl buffer for 30 min), and then in DAB supplemented with 0.01% hydrogen peroxide for 20 min. Slides were dehydrated in increasing concentrations of ethanol and mounted in DePeX (BDH). Control slides were incubated in non-immune rabbit IgG as for primary antibodies.
Primary antibodies and final concentration: Krox20 (Babco, Richmond, CA, USA): 25 µg/ml; myelin basic protein I (MBP; Dako): 25 µg/ml; S100 (Dako): 50 µg/ml; galactocerebroside (GalC; Sigma): 50 µg/ml; and non-immune rabbit IgG (Jackson).
Anaesthesia of mice
Mice were anaesthetized by intraperitoneal injections of ketamine (Imalgene®, 5–10 µg/g) and xylazine (Rompun®, 4–7 µg/g). These anaesthetics are stable over time and have moderate effects on muscle contraction (Ingalls et al., 1996). Animals were warmed by an infra-red lamp until they recovered from the narcosis.
EMG recordings and stimulations
Electrical stimulation of the foot was delivered by means of stainless steel wires pricked into the paw pads (twin pulses of 6 V, 0.1-ms long at 500 Hz, every 20 s). This stimulation evoked reflex responses in hindlimbs consisting of an ipsilateral flexion and a contralateral extension. EMG recordings were made from the contralateral gastrocnemius muscle (ankle extensor muscle) by means of nickel-chrome wires of 50 µm diameter. The recording electrode was inserted through the skin into the muscle, parallel to the muscle fibres. A reference electrode was placed in the skin of the back. Signals were amplified, filtered (AC-coupled amplifiers, bandwidth 70 Hz–1 kHz), digitized and stored on a hard disk (Clampex 7 software, Axon Instruments; sampling frequency of 20 kHz). Subsequent analysis consisted in rectifying and averaging (n = 50) the EMG activities (Clampfit 7 software, Axon Instruments). The latency of the motor response was measured to indicate the conduction velocity of sensory and motor fibres involved in the reflex.
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Before presenting our results, we will make an outline of the characteristics of the murine transgenic line used. The C22 line (seven integrated YAC copies,
210% overexpression) presents a severe peripheral neuropathy, with only a few onion bulbs, characterized by a lack of myelin in most adult nerve fibres (Huxley et al., 1996, 1998).
Morphometric studies of myelination in PMP22-overexpressing mice
Transverse semi-thin sections of sciatic nerves from C22 and control mice were obtained at P0, P3, P7 and P16. Fixation of nerves with osmium tetroxide and potassium ferrocyanide allowed good visualization of the myelin sheath at the light microscopy level on non-counterstained slides. The axonal diameter and the thickness of the myelin sheath were evaluated on digitized pictures. Scatter plots of myelin sheath thickness versus axonal diameter were drawn (Fig. 1A). At P7, myelination was already observed in nerves from control mice (myelin sheath thickness from 0.33 to 1.51 µm), as well as in nerves from transgenic mice. However, when myelinated, the CMT axons exhibited very thin myelin sheaths (<0.4 µm). The same phenomenon was also observed at P16. The comparison using 
2 test between histograms of axonal diameters and those of myelin sheath thickness also demonstrated that myelination just began in nerve from transgenic mice at P7, proceeded at a lower rate than in nerve from control mice, was restricted to small diameter axons and did not concern large calibre axons (not shown).
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An estimation of the percentage of myelinated versus unmyelinated fibres, measured at different stages, is presented in Fig. 2. Before P6, as myelination had not started, no difference was observed between normal and transgenic mice. At P7, myelination had started in
40% of the fibres of the control mice, while only a few fibres showed a myelin sheath in pathological nerves (<10%). At P16, myelination was largely engaged in numerous fibres (>80% of fibres exhibited a myelin sheath) of the control nerves, whereas only a few fibres (17% on average) exhibited a myelin sheath in pathological nerves. Moreover, the myelin sheath seemed thinner in pathological nerves fibres than in controls. We observed that the only myelinated fibres in pathological nerves were small diameter axons. Large diameter axons appeared to remain unmyelinated. This has already been observed in adult transgenic mice, with a proportion of unmyelinated fibres that was almost identical to the one we observed at P16 (Huxley et al., 1998).
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These results show that only a small percentage of fibres have correctly been engaged in the myelination process in the C22 line.
Electron microscopy analysis of normal and pathological sciatic nerves
Electron microscopy techniques were used to analyse the normal and pathological sciatic nerves (Fig. 3). The aspects of pathological and normal nerves were not significantly different at P0. At P3, myelination had started in normal animals but not in C22 animals. Unlike control mice, transgenic C22 mice presented a majority of unmyelinated large axons at P6 and P16. Few small diameter axons were myelinated between P3 and P16. We also observed numerous figures of aborted tentative myelination by Schwann cells. This suggests that the last steps of the myelination program of Schwann cells are impaired in CMT mice. In addition, no signs of demyelination, accumulation of debris and abnormal macrophagic activity were observed.
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EMG data
The age-related increase of axonal conduction velocity is mostly due to myelin formation. We physiologically analysed the myelination process in control and C22 mice by measuring the motor latency evoked in a distal limb muscle by electrical stimulation of the contralateral foot at different ages. This reflex involved the conduction velocity of sensory and motor fibres. An 85% reduction in latency was observed in control mice from birth to adulthood. The amplitude of the EMG response depended on the position of the recording electrode in the muscular fascia. Therefore, we analysed only the latency of motor responses (Fig. 4D). The latency at the end of the third week was very close to adult values, suggesting that myelination was almost completed at that time. Latencies were similar in control and C22 mice during the first post-natal week. However, the age-related decrease in latency was much less pronounced in C22 mice than in control animals, leading to a significant difference between the two groups of animals as early as the second week after birth (P < 0.01; P < 0.001, in adults).
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Expression of markers in normal and CMT mice
The above results demonstrate clearly that PMP22 overexpression results in an abnormal process of myelination and raise the question of the function of PMP22 in the myelination process. Moreover, they also raise the question of the differentiation status of the Schwann cells that overexpress PMP22. To answer these questions, we determined, from birth to P16, the pattern of expression of markers (Krox20, GalC and MBP) in Schwann cells of normal and pathological mice.
The expression of GalC and MBP in C22 sciatic nerves was very low, confirming that the myelination program has not been set up in most of the pathological Schwann cells. An interesting point came from the expression of Krox20 in normal and pathological conditions. In normal Schwann cells the expression of the Krox20 transcription factor was increased during the myelination process. Conversely, we observed a lack of expression of Krox20 in most of the Schwann cells overexpressing PMP22 (Fig. 5A and B). Surprisingly, only a few nuclei seemed to express this marker.
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Fibroblasts and collagen expression
Using electronic microscopy in pathological nerves, we observed the presence of numerous hyperactive fibroblasts, with an enlarged endoplasmic reticulum, and actively running collagen (Fig. 6). This phenomenon was observed during all stages after birth. We thus analysed the endoneural areas occupied by collagen in normal and pathological nerves on scanned electron microscope pictures. Image analysis showed pathological nerves containing more collagen than controls (data not shown).
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Discussion |
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Our results show that PMP22 overexpression interferes with the myelination program of murine Schwann cells, normally occurring between P0 and P16. Only a few fibres were myelinated in the transgenic mice line presenting the highest PMP22 overexpression (C22). These data raise two questions: why do some fibres seem to escape the repression of the myelination process and nevertheless present a myelin sheath, and which molecular process is involved in this absence of myelination in most of the Schwann cells?
Regarding the first question, note that the only fibres with myelin in C22 have a small diameter. It therefore seems that the impairment of the myelination process affects mainly large axons. This has also been observed in CMT1A patients and in other models of the disease (Sancho et al., 1999), and strongly suggests that it did not result from a preferential demyelination of large axon, but from a preferential defect in myelination of these large axons during the ontogenesis of peripheral nerves.
Concerning the second question, the pattern of expression of some markers gives a clue to the molecular process involved. It appears that PMP22 overexpression leads to the repression of transcription factors such as Krox20 expressed in myelinating Schwann cells. These results, together with the lack of expression of S100 and MBP, strongly suggest that PMP22 expression is involved in the correct setting up of the myelination process. Overexpression of the gene blocks the pathological Schwann cells in an immature non myelinating stage.
The biological role of the PMP22 protein has not been elucidated so far, although several hypotheses have been proposed (Carenini et al., 1999). It has been suggested that PMP22 is involved in the process of myelin compaction (Adlkofer et al., 1995). Our data, although they do not demonstrate the definite function of this protein, strongly suggest that it is involved directly, or indirectly, in the control of the final process of maturation of Schwann cells, leading to the formation of the myelin sheath, and not only in the structural maintenance of this structure. Note that this protein is a four-domain transmembrane protein exhibiting, like connexin 32 (Cx32), a small extracellular domain (Taylor et al., 2000). This raises the question of the function of PMP22 in a signalling pathway, which could be involved in the maturation process of myelinating Schwann cells. One clue could be the relationship between PMP22 expression, linked with growth arrest, and the expression of the ‘maturation program’ of myelinating Schwann cells.
Our data show that, whatever the underlying mechanism, PMP22 overexpression is associated with a dysmyelination process and not only with a demyelination–remyelination (D’Urso et al., 1998). Since these two processes are not mutually exclusive, we suspect that both of them may occur, depending on the stage of evolution of the disease. In CMT1A patients these mechanisms are uncertain, due to the lack of information on the physiopathological processes in the presymptomatic phases of the disorder. However, a report from Berciano and colleagues established that the reduction in nerve conduction velocity is present in young individuals carrying the CMT1A duplication, before the appearance of any clinical signs (Berciano et al., 2000). This probably means that PMP22 overexpression interacts with the myelination process in humans also.
The progression of the disorder, in particular the locomotor disabilities, can be associated with a secondary effect such as fibre loss, and not with the primary effect, dysmyelination, as it seems that effects on myelination precedes the locomotor impairment, sometime for a long period (Krajewski et al., 2000).
These observations open up new horizons with regard to treatment of the disease. It may be focused on PMP22 overexpression, and on the earliest stages of the myelination process.
Concerning the anomalies we observed in fibroblasts and collagen deposition, it is not really surprising that fibroblasts are affected by PMP22 overexpression, as the gene was first characterized in fibroblasts as a growth arrest gene. Moreover, collagen overexpression in peripheral nerves can explain the hypertrophy of these nerves, a feature that has already been observed by clinicians. The pattern of collagenization in neuropathic peripheral nerves is also modified in other types of neuropathies such as in hereditary motor and sensory neuropathy-Lom in humans (King et al., 1999) or in distal sensorimotor polyneuropathy seen in mature Rottweiler dogs (Braund et al., 1994), where the amount of endoneurial collagen is markedly increased. As the anomaly in collagen deposition is observed before myelination, extracellular matrix and basal lamina are likely involved in the phenotype. If this is true, the perturbation of the interaction of Schwann cells with extracellular matrix could be the major factor in myelination defect. Further investigation of this hypothesis may lead to potential therapeutic strategies.
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Acknowledgements |
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This work was supported by the AFM, and D.S.-D. is recipient of an AFM (Association Française contre les Myopathies) postdoctoral fellowship.
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References |
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