A mouse embryonic stem cell model of Schwann cell differentiation for studies of the role of neurofibromatosis type 1 in Schwann cell development and tumor formation

The neurofibromatosis Type 1 (NF1) gene functions as a tumor suppressor gene. One known function of neurofibromin, the NF1 protein product, is to accelerate the slow intrinsic GTPase activity of Ras to increase the production of inactive rasGDP, with wide-ranging effects on p21ras pathways. Loss of neurofibromin in the autosomal dominant disorder NF1 is associated with tumors of the peripheral nervous system, particularly neurofibromas, benign lesions in which the major affected cell type is the Schwann cell (SC). NF1 is the most common cancer predisposition syndrome affecting the nervous system. We have developed an in vitro system for differentiating mouse embryonic stem cells (mESC) that are NF1 wild type (+/+), heterozygous (+/-), or null (-/-) into SC-like cells to study the role of NF1 in SC development and tumor formation. These mES-generated SC-like cells, regardless of their NF1 status, express SC markers correlated with their stage of maturation, including myelin proteins. They also support and preferentially direct neurite outgrowth from primary neurons. NF1 null and heterozygous SC-like cells proliferate at an accelerated rate compared to NF1 wild type; this growth advantage can be reverted to wild type levels using an inhibitor of MAP kinase kinase (Mek). The mESC of all NF1 types can also be differentiated into neuron-like cells. This novel model system provides an ideal paradigm for studies of the role of NF1 in cell growth and differentiation of the different cell types affected by NF1 in cells with differing levels of neurofibromin that are neither transformed nor malignant.     

Activation of cannabinoid receptor 2 attenuates mechanical allodynia and neuroinflammatory responses in a chronic post‐ischemic pain model of complex regional pain syndrome type I in rats

Complex regional pain syndrome type 1 (CRPS‐I) remains one of the most clinically challenging neuropathic pain syndromes and its mechanism has not been fully characterized. Cannabinoid receptor 2 (CB2) has emerged as a promising target for treating different neuropathic pain syndromes. In neuropathic pain models, activated microglia expressing CB2 receptors are seen in the spinal cord. Chemokine fractalkine receptor (CX3CR1) plays a substantial role in microglial activation and neuroinflammation. We hypothesized that a CB2 agonist could modulate neuroinflammation and neuropathic pain in an ischemia model of CRPS by regulating CB2 and CX3CR1 signaling. We used chronic post‐ischemia pain (CPIP) as a model of CRPS‐I. Rats in the CPIP group exhibited significant hyperemia and edema of the ischemic hindpaw and spontaneous pain behaviors (hindpaw shaking and licking). Intraperitoneal administration of MDA7 (a selective CB2 agonist) attenuated mechanical allodynia induced by CPIP. MDA7 treatment was found to interfere with early events in the CRPS‐I neuroinflammatory response by suppressing peripheral edema, spinal microglial activation and expression of CX3CR1 and CB2 receptors on the microglia in the spinal cord. MDA7 also mitigated the loss of intraepidermal nerve fibers induced by CPIP. Neuroprotective effects of MDA7 were blocked by a CB2 antagonist, AM630. Our findings suggest that MDA7, a novel CB2 agonist, may offer an innovative therapeutic approach for treating neuropathic symptoms and neuroinflammatory responses induced by CRPS‐I in the setting of ischemia and reperfusion injury.     

c-Kit receptor expression in normal human Schwann cells and Schwann cell lines derived from neurofibromatosis type 1 tumors

The growth factor receptor c-Kit has several well-characterized functions during the development of numerous cell types, including red blood cells, mast cells, and melanocytes. Its role in Schwann cells has been described in transformed cells derived from malignant peripheral nerve sheath tumors from patients with neurofibromatosis type 1 (NF1 MPNST; Badache et al. [1998] Oncogene 17:795-800). However, c-Kit functions have not been investigated in normal Schwann cells. We report here that neonatal rat Schwann cells express low c-Kit levels, whereas expression levels for c-Kit are high for Schwann cells derived from MPNST of NF1 patients. In addition, c-Kit expression is not detectable in normal adult human Schwann cells. Although the c-Kit ligand stem cell factor (SCF) induces the phosphorylation of protein kinase B (or Akt) and prevents apoptosis in Schwann cells, SCF has no effect on the proliferation or differentiation of Schwann cells.     

Isolation and age-related characterization of mouse Schwann cells from dorsal root ganglion explants in type I collagen gels

A technique for isolation of adult Schwann cells (ScC) from dorsal root ganglia (DRG) is described. Decapsulated DRG explants embedded into type I collagen gels were cultured for 3 days in serum-free medium during which ScC migrated from the explant. These explants were then grown in serum-supplemented medium to allow ScC proliferation. On day 10 the number of ScC isolated from DRG explants per mouse was about 2.5 × 10⁵, and the purity was greater than 95%. This culture system provided sufficient numbers of highly purified adult ScC in a shorter culture period (2–3 times) than other methods. We used ScC from this method to determine the age-related changes in attachment, growth, and survival of ScC cultured in serum-free medium. The attachment capacity of adult ScC on type I collagen or polylysine was similar to that of newborn ScC. However, the collagen promoted growth and survival of adult ScC but not that of neonatal ScC, indicating age-related differences of ScC properties in vitro. © 1993 Wiley-Liss, Inc.     

Macrophages influence Schwann cell myelin autophagy after nerve injury and in a model of Charcot-Marie-Tooth disease

Background and Aims

The complex cellular and molecular interactions between Schwann cells (SCs) and macrophages during Wallerian degeneration are a prerequisite to allow rapid uptake and degradation of myelin debris and axonal regeneration after peripheral nerve injury. In contrast, in non-injured nerves of Charcot-Marie-Tooth 1 neuropathies, aberrant macrophage activation by SCs carrying myelin gene defects is a disease amplifier that drives nerve damage and subsequent functional decline. Consequently, targeting nerve macrophages might be a translatable treatment strategy to mitigate disease outcome in CMT1 patients. Indeed, in previous approaches, macrophage targeting alleviated the axonopathy and promoted sprouting of damaged fibers. Surprisingly, this was still accompanied by robust myelinopathy in a model for CMT1X, suggesting additional cellular mechanisms of myelin degradation in mutant peripheral nerves. We here investigated the possibility of an increased SC-related myelin autophagy upon macrophage targeting in Cx32def mice.

Methods

Combining ex vivo and in vivo approaches, macrophages were targeted by PLX5622 treatment. SC autophagy was investigated by immunohistochemical and electron microscopical techniques.

Results

We demonstrate a robust upregulation of markers for SC autophagy after injury and in genetically-mediated neuropathy when nerve macrophages are pharmacologically depleted. Corroborating these findings, we provide ultrastructural evidence for increased SC myelin autophagy upon treatment in vivo.

Interpretation

These findings reveal a novel communication and interaction between SCs and macrophages. This identification of alternative pathways of myelin degradation may have important implications for a better understanding of therapeutic mechanisms of pharmacological macrophage targeting in diseased peripheral nerves.     

Adoptive transfer of peripheral immune cells potentiates allodynia in a graded chronic constriction injury model of neuropathic pain

Recent evidence demonstrates that peripheral immune cells contribute to the nociceptive hypersensitivity associated with neuropathic pain by infiltrating the central nervous system (CNS). We have recently developed a rat model of graded chronic constriction injury (CCI) by varying the exposure of the sciatic nerve and control non-nerve tissue to surgical placement of chromic gut. We demonstrate that splenocytes can contribute significantly to CCI-induced allodynia, as adoptive transfer of these cells from high pain donors to low pain recipients potentiates allodynia (P < 0.001). The phenomenon was replicated with peripheral blood mononuclear cells (P < 0.001). Adoptive transfer of allodynia was not achieved in sham recipients, indicating that peripheral immune cells are only capable of potentiating existing allodynia, rather than establishing allodynia. As adoptively transferred cells were found by flow cytometry to migrate to the spleen (P < 0.05) and potentiation of allodynia was prevented in splenectomised low pain recipients, adoptive transfer of high pain splenocytes may induce the migration of host-derived immune cells from the spleen to the CNS as observed by flow cytometry (P < 0.05). Importantly, intrathecal transfer of CD45⁺ cells prepared from spinal cords of high pain donors into low pain recipients led to potentiated allodynia (P < 0.001), confirming that infiltrating immune cells are not passive bystanders, but actively contribute to nociceptive hypersensitivity in the lumbar spinal cord.     

Schwann cell-derived CXCL1 contributes to human immunodeficiency virus type 1 gp120-induced neuropathic pain by modulating macrophage infiltration in mice

The neuroinflammatory responses to human immunodeficiency virus type 1 (HIV-1) coat proteins, such as glycoprotein 120 (gp120), are considered to be responsible for the HIV-associated distal sensory neuropathy. Accumulating evidences suggest that T-cell line tropic X4 gp120 increases macrophage infiltration into the peripheral nerves, and thereby induces neuroinflammation leading to pain. However, the mechanisms underlying X4 gp120-induced macrophage recruitment to the peripheral nervous systems remain unclear. Here, we demonstrated that perineural application of X4 gp120 from HIV-1 strains IIIB and MN elicited mechanical hypersensitivity and spontaneous pain-like behaviors in mice. Furthermore, flow cytometry and immunohistochemical studies revealed increased infiltration of bone marrow-derived macrophages into the parenchyma of sciatic nerves and dorsal root ganglia (DRG) 7 days after gp120 IIIB or MN application. Chemical deletion of circulating macrophages using clodronate liposomes markedly suppressed gp120 IIIB-induced pain-like behaviors. In in vitro cell infiltration analysis, RAW 264.7 cell (a murine macrophage cell line) was chemoattracted to conditioned medium from gp120 IIIB- or MN-treated cultured Schwann cells, but not to conditioned medium from these gp120-treated DRG neurons, suggesting possible involvement of Schwann cell-derived soluble factors in macrophage infiltration. We identified using a gene expression array that CXCL1, a chemoattractant of macrophages and neutrophils, was increased in gp120 IIIB-treated cultured Schwann cells. Similar to gp120 IIIB or MN, perineural application of recombinant CXCL1 elicited pain-like behaviors accompanied by macrophage infiltration to the peripheral nerves. Furthermore, the repeated injection of CXCR2 (receptor for CXCL1) antagonist or CXCL1 neutralizing antibody prevented both pain-like behaviors and macrophage infiltration in gp120 IIIB-treated mice. Thus, the present study newly defines that Schwann cell-derived CXCL1, secreted in response to X4 gp120 exposure, is responsible for macrophage infiltration into peripheral nerves, and is thereby associated with pain-like behaviors in mice. We propose herein that communication between Schwann cells and macrophages may play a prominent role in the induction of X4 HIV-1-associated pain.     

Schwann cell differentiation in Charcot-Marie-Tooth disease type 1A (CMT1A): normal number of myelinating Schwann cells in young CMT1A patients and neural cell adhesion molecule expression in onion bulbs

Charcot-Marie-Tooth disease type 1A (CMT1A) is a common hereditary demyelinating neuropathy caused by a duplication of the gene for the myelin protein PMP22, resulting in overexpression of PMP22 in young patients. Although genetically well defined, the pathogenesis of the hereditary demyelinating neuropathy CMT1A is still unclear. Homology of PMP22 cDNA to the growth arrest-specific gene gas3 and experiments in vitro showing decreased proliferation in PMP22-overexpressing Schwann cells suggest a role of PMP22 in Schwann cell differentiation. Furthermore, overexpression of PMP22 in fibroblasts induces programmed cell death. In this report we applied morphometrical methods using electron micrographs and immunohistochemistry to further characterise Schwann cells in CMT1A nerve biopsy samples from CMT1A patients. We show that the total number of PMP22-expressing Schwann cells, i.e. Schwann cells that are in a 1:1 relationship with axons, was not reduced in sural nerve biopsy samples from six young CMT1A patients. We excluded non-specific secondary Schwann cell proliferation. Thus, in young CMT1A patients with increased PMP22 overexpression there seems to be no evidence for altered initial Schwann cell proliferation in achieving a 1:1 relationship to axons prior to the process of de- and remyelination. Further, using electron microscopy we found no evidence for apoptosis of Schwann cells in CMT1A . However, we provide additional support for an abnormal Schwann cell phenotype in CMT1A by showing the expression of neural cell adhesion molecule immunoreactivity in onion bulbs. Thus, the role of PMP22 in cell growth and differentiation does not lead to an altered number of myelinating Schwann cells but to altered Schwann cell differentiation in CMT1A. Received: 23 September 1996 / Revised: 28 November 1996, 31 January 1997, 2 April 1997 / Accepted: 3 April 1997     

Comparison of Schwann cell and sciatic nerve transcriptomes indicates that mouse is a valid model for the human peripheral nervous system

High-throughput gene expression analyses of murine models of the peripheral nervous system (PNS), and its cellular components, have yielded enormous amounts of expression data of the PNS in various conditions. These data provided clues for future research directions to further decipher this complex organ in relation to acquired and inherited PNS diseases. Various studies addressing the validity of mouse models for human conditions in other tissues and cell types have indicated that in many cases the mouse model only poorly represents the human situation. To determine how well the mouse can serve as model to study the biological processes occurring in the PNS, we compared the gene expression profiles that we generated for mouse and human sciatic nerve and cultured Schwann cells derived thereof. A two-way analysis based on the differentially expressed genes between the sciatic nerve and the cultured Schwann cell, and which takes into account the differential expression between mouse and man, indicates that the human PNS is well represented by that of the mouse in terms of the "biological processes" ontology.     

Intrathecal administration of an NMDA or a non-NMDA receptor antagonist reduces mechanical but not thermal allodynia in a rodent model of chronic central pain after spinal cord injury

Spinal cord injuries (SCI) result in a devastating loss of function and chronic central pain syndromes frequently develop in the majority of these patients. The present study uses a rodent spinal hemisection model of SCI in which mechanical and thermal allodynia develops by 24 days after injury. Post-operative paw withdrawal responses to low threshold and high threshold mechanical stimuli compared to pre-operative responses (4.78, 9.96, and 49.9 mN) were increased and were statistically significant (p<0.05) for both forelimbs and hindlimbs indicating the development of mechanical allodynia. By contrast, post-operatively, the temperature at which paw withdrawal accompanied by paw lick occurred was significantly decreased (p<0.05), indicating the development of thermal allodynia. The intrathecal application of either D-AP5, a competitive NMDA receptor antagonist, or NBQX-disodium salt, a competitive non-NMDA AMPA/kainate receptor antagonist, alleviated the mechanical allodynia and lowered the threshold of response for the high threshold mechanical stimuli in a dose-dependent manner, and these decreases were statistically significant (p<0.05). By contrast, neither the D-AP5 nor the NBQX produced a statistically significant change in the thermal allodynia behavior in either forelimbs or hindlimbs in the hemisected group. No significant changes in locomotion scores, and thus no sedation, were demonstrated by the hemisected group for the doses tested. These data support the potential efficacy of competitive excitatory amino acid receptor antagonists in the treatment of chronic central pain, particularly where input from low threshold mechanical afferents trigger the onset of the painful sensation. Furthermore, these data suggest a role for both NMDA and non-NMDA receptors in the development of plastic changes in the spinal cord that provide the underlying mechanisms for central neuropathic pain.     

Perisynaptic Schwann cells phagocytose nerve terminal debris in a mouse model of Guillain‐Barré syndrome

In mouse models of acute motor axonal neuropathy, anti‐ganglioside antibodies (AGAbs) bind to motor axons, notably the distal nerve, and activate the complement cascade. While complement activation is well studied in this model, the role of inflammatory cells is unknown. Herein we aimed to investigate the contribution of phagocytic cells including macrophages, neutrophils and perisynaptic Schwann cells (pSCs) to distal nerve pathology. To observe this, we first created a subacute injury model of sufficient duration to allow inflammatory cell recruitment. Mice were injected intraperitoneally with an anti‐GD1b monoclonal antibody that binds strongly to mouse motor nerve axons. Subsequently, mice received normal human serum as a source of complement. Dosing was titrated to allow humane survival of mice over a period of 3 days, yet still induce the characteristic neurological impairment. Behaviour and pathology were assessed in vivo using whole‐body plethysmography and post‐sacrifice by immunofluorescence and flow cytometry. ex vivo nerve‐muscle preparations were used to investigate the acute phagocytic role of pSCs following distal nerve injury. Following complement activation at distal intramuscular nerve sites in the diaphragm macrophage localisation or numbers are not altered, nor do they shift to a pro‐ or anti‐inflammatory phenotype. Similarly, neutrophils are not significantly recruited. Instead, ex vivo nerve‐muscle preparations exposed to AGAb plus complement reveal that pSCs rapidly become phagocytic and engulf axonal debris. These data suggest that pSCs, rather than inflammatory cells, are the major cellular vehicle for axonal debris clearance following distal nerve injury, in contrast to larger nerve bundles where macrophage‐mediated clearance predominates.     

Peripheral sympathetic function as a predictor of complex regional pain syndrome type I (CRPS I) in patients with radial fracture

Complex regional pain syndrome type I (CRPS I) is a frequent complication after injuries of the upper limbs. The pathophysiology of this disease remains unclear, although disturbances of the sympathetic nervous system have been detected in several clinical studies, and sympathetic blocks resolve the symptoms in many of the cases. To investigate the meaning of sympathetic dysfunction at the beginning of the disease, 27 patients with distal radial fracture were examined prospectively during the course of the disease with regard to their clinical symptoms and their peripheral sympathetic nervous function. Sympathetic nervous function was examined by testing the vasoconstrictor response to sympathetic stimuli--recorded with laser Doppler fluxmetry--of the fingertips of both hands. Four patients developed CRPS I during the 12-week observation time and two patients presented an incomplete clinical CRPS I picture ('borderline patients'). The complaints of all patients (normal fracture patients, CRPS I patients, borderline patients) were similar during the first week after trauma with focus on pain, motoric disturbances and autonomic symptoms. After 1 or 2 weeks, a larger clinical difference developed between normal fracture patients and CRPS I or 'borderline patients'. In CRPS I patients and 'borderline patients', the sympathetic vasoconstrictor response was diminished or absent from the first posttraumatic day throughout the observation time, whereas the normal fracture patients revealed slightly impaired sympathetic nervous function on the first posttraumatic day and normal results during the rest of the observation time. With regard to the unaffected contralateral hand, CRPS I patients also showed impaired sympathetic nervous function. The results of the present study suggest that the disturbances in the sympathetic nervous system in CRPS I patients are systemic and not limited to the affected limb. Their occurrence before the clinical breakout of the disease may serve as a marker that might be useful for early therapy and lead to further understanding of the pathophysiology of CRPS I.     

Thermal thresholds in complex regional pain syndrome type I: sensitivity and repeatability of the methods of limits and levels.

OBJECTIVES: To study whether the method of levels (MLE) or the method of limits (MLI) is preferable as a method of measuring thermal perception thresholds in patients with complex regional pain syndrome type I (CRPS I). METHODS: Perception thresholds for warmth and cold were measured twice, with both MLE and MLI, at a 1 month interval, both at unaffected and affected wrists (n=33) or feet (n=20) of patients with CRPS I of one extremity. RESULTS: (1) Sensitivity for pathology was equal for both methods. (2) The agreement between thresholds measured by both methods was low at all locations, except for the unaffected wrist. Since thresholds measured with the MLI always contain reaction time artefacts, this lack of agreement favours the MLE. (3) At both unaffected and affected wrists, the MLE showed significantly better coefficients of repeatability as compared to the MLI for both sensations. However, at both unaffected and affected feet, there was no preference for either method as far as threshold measurement repeatability was concerned. CONCLUSIONS: Abnormal thermal perception thresholds occurred in 20% (foot) to 36% (wrist) of the CRPS I patients on the affected side and in 15% (foot, wrist) on the unaffected side. The MLE is considered to be the preferable method to assess thermal perception thresholds in CRPS I.     

The effect of upper-extremity aerobic exercise on complex regional pain syndrome type I: a randomized controlled study on subacute stroke

Abstract

Background and purpose:

Complex regional pain syndrome type I (CPRS I), is a complex of symptoms characterized by diffuse pain usually with associated swelling, vasomotor instability, and severe functional impairment of the affected extremity in stroke patients. Pain is a prominent feature and is often refractory to variety of treatment.

Methods:

To investigate the clinical, functional, and psychosocial effects of upper extremity aerobic exercise (UEAE) and compare the effect of aerobic exercise with that of conventional physiotherapy in patients with CPRS type I following stroke as a randomized controlled assesor blinded 4?week-study. A total of 52 inpatients with stroke [mean age: 65.95?±?8.7 (min.?=?53, max.?=?80) years, and the mean age of the control group was 67.50?±?11.2?years], all within 6?months post-stroke and diagnosed with CPRS I. The UEAE program consisted of an arm crank ergometer (10?W/min), in addition to a conventional physiotherapy (whirlpool, TENS, retrograd massage). Primary outcome measures were CPRS clinical determinants (pain, hyperalgesia, allodynia, and autonomic abnormalities) secondary outcome measures were functional independence measure (FIM), Nottingham Health Profile (NHP), and Beck Depression Scale scores that were performed at 0?month (baseline) and 4?weeks (post-treatment).

Results:

In UEAE group, patients reported significant pain relief (89.9%) and significant decline in CRPS signs and symptoms. The mean change in pain at shoulder, pain at the hand as well as and NHP and BDS scores between groups were statistically significant (P?<?0.05).

Conclusions:

UEAE made an excellent improvement in the symptoms and signs of CRPS I. Combined treatment of conventional physiotherapy and aerobic exercises may be an excellent synthesis for this syndrome in these patients.     

Overexpression of ErbB2 and ErbB3 receptors in Schwann cells of patients with Charcot-Marie-tooth disease type 1A

Axon-derived neuregulins (NRGs) are a family of growth factors whose binding to ErbB tyrosine kinase receptors promotes the maturation, proliferation and survival of Schwann cells (SCs). Correct NRG/ErbB signaling is essential for the homeostasis of axonal-glial complexes and seems to play a role in peripheral nerve repair. The potential involvement of ErbB receptors in human peripheral neuropathies has not been clarified. Therefore, we assessed the immunoreactivity for EGFR (ErbB1), ErbB2, and ErbB3 in nerve biopsies from patients with different forms of Charcot-Marie-Tooth disease, type 1, (CMT1), as compared to others with inflammatory neuropathies and controls. The most notable changes consisted in the overexpression of ErbB2 and ErbB3 by SCs of nerves from CMT1A patients. These findings are consistent with an impairment of SC differentiation and expand the molecular phenotype of CMT1A. The upregulation of these receptors may play a role in the inhibition of myelination or in the promotion of recurrent demyelination and axonal damage.     

High-mobility group box 1 contributes to mechanical allodynia and spinal astrocytic activation in a mouse model of type 2 diabetes

Chronic pain is one of the most common complications of diabetes. However, current treatments for diabetic pain are usually unrealistic because the underlying mechanisms are far from being clear. Immerging studies have implicated immune factors as key players in the diabetic pain. High-mobility group box 1 (HMGB1) is an important mediator of inflammatory response, but its role in diabetic pain is unclear. In the present study, we observed that db/db mice (a model of type 2 diabetes) developed persistent mechanical allodynia from postnatal 2 months. Western blot showed that in postnatal 2-5 months, HMGB1 was significantly higher than that of the heterozygous littermates (db/+) mice. Intrathecal injection of a HMGB1 neutralizing antibody (anti-HMGB1) inhibited mechanical allodynia. Immunostaining data showed that compared with db/+ and C57 mice (postnatal 4 months), glial fibrillary acidic protein (GFAP) staining was significantly increased in the spinal cord of db/db mice. Anti-HMGB1 could effectively decrease GFAP expression. Real-time PCR showed that in postnatal 4 months, db/db mice induced significant increases of TNF-alpha, IL-1β, IL-6 and monocyte chemoattractant protein-1 (MCP-1) in the spinal dorsal horn, while anti-HMGB1 (50 μg) effectively inhibited the up-regulation of these inflammatory mediators. Our results indicate that HMGB1 is significantly up-regulated in the spinal cord of type 2 diabetes, and inhibiting HMGB1 may provide a novel treatment for diabetic pain.     

The α-chemokine CXCL14 is up-regulated in the sciatic nerve of a mouse model of Charcot–Marie–Tooth disease type 1A and alters myelin gene expression in cultured Schwann cells

At present the pathogenesis of CMT1A neuropathy, caused by the overexpression of PMP22, has not yet been entirely understood. The PMP22-overexpressing C61 mutant mouse is a suitable animal model, which mimics the human CMT1A disorder. We observed that myelin gene expression in the sciatic nerve of the C61 mouse was up-regulated at postnatal day 4 to 7 (P4–P7). When investigating the morphology of peripheral nerves in C61 and wildtype mice at early stages of postnatal development, hypermyelination could be detected in the femoral quadriceps and sciatic nerve of transgenic animals at postnatal day 7 (P7). In order to identify genes, other than Pmp22, that are modulated in sciatic nerve of P7 transgenic mice, we applied microarray technology. Amongst the regulated genes, the gene encoding the α-chemokine CXCL14 was most prominently up-regulated. We report that Cxcl14 was expressed exclusively by Schwann cells of the sciatic nerve, as well as by cultured Schwann cells triggered to differentiate. Furthermore, in cultured Schwann cells CXCL14 modulated the expression of myelin genes and altered cell proliferation. Our findings demonstrate that early overexpression of PMP22, in a mouse model of CMT1A, results in a strong up-regulation of CXCL14, which seems to play a novel regulatory role in Schwann cell differentiation.