Genome-wide analysis of EGR2/SOX10 binding in myelinating peripheral nerve.

Myelin is essential for the rapidity of saltatory nerve conduction, and also provides trophic support for axons to prevent axonal degeneration. Two critical determinants of myelination are SOX10 and EGR2/KROX20. SOX10 is required for specification of Schwann cells from neural crest, and is required at every stage of Schwann cell development. Egr2/Krox20 expression is activated by axonal signals in myelinating Schwann cells, and is required for cell cycle arrest and myelin formation. To elucidate the integrated function of these two transcription factors during peripheral nerve myelination, we performed in vivo ChIP-Seq analysis of myelinating peripheral nerve. Integration of these binding data with loss-of-function array data identified a range of genes regulated by these factors. In addition, although SOX10 itself regulates Egr2/Krox20 expression, leading to coordinate activation of several major myelin genes by the two factors, there is a large subset of genes that are activated independent of EGR2. Finally, the results identify a set of SOX10-dependent genes that are expressed in early Schwann cell development, but become subsequently repressed by EGR2/KROX20.

Root canal irrigation system using remotely generated high-power ultrasound.

Root canal treatment is performed to remove the bacteria proliferating in the root canals of a tooth. Many conventional root canal irrigation methods use an instrument inserted into the root canals. However, bacteria removal is often incomplete in the apical region of the root canal, and the treatment carries clinical risks, such as instrument fracture and extrusion of irrigation liquid through the canal apex. We here suggest a novel, remotely generated high-intensity ultrasound irrigation system that exhibits better irrigation performance and a reduced clinical risk. Our device employs powerful ultrasonic waves generated by a transducer placed outside a target tooth. The generated ultrasonic waves are guided to travel into the root canals. In the root canals of the target tooth, acoustic cavitation occurs, and vapor bubbles are created. The dynamic motions of vapor bubbles create remarkable cleaning effects. Using root canal models, we tested the cleaning performance of the proposed system and compared it with other conventional irrigation methods. The results revealed that biofilm in the apical region of the root canal models can be removed exclusively using the proposed system, thus demonstrating an improvement in cleaning performance. We also measured pressure at the apex of the root canals of an extracted tooth while operating the proposed system. Our system exhibited a smaller pressure compared to the syringe irrigation method, thus suggesting a reduced risk of apical extrusion of the irrigation liquid. Since the proposed system operates without inserting instruments into the root canal, it can clean multiple root canals in a tooth simultaneously with a single treatment. The proposed device would be a breakthrough in root canal treatment in terms of irrigation performance, clinical safety, and ease of treatment.

Relationship between fatigue severity scale and occupational injury in Korean workers.

BACKGROUND: The aim of this study is to investigate the relationship between fatigue and occupational injury. METHODS: This study was conducted at a university hospital in 2014 and 2015. In 2014, the fatigue severity scale (FSS) was used to evaluate workers' fatigue levels. Later, when the same workers were examined in 2015, a questionnaire survey was conducted to determine whether they had experienced absences or treatment for work-related accidents. The χ2 test was used to analyse the relationship between demographic characteristics, fatigue levels, and occupational injuries. After controlling for confounders, a logistic regression analysis was performed to calculate the odds ratios (ORs). RESULTS: In 2014, 19,218 workers were screened during health examination and their fatigue level were evaluated using FSS questionnaires. in 2015, workers' occupational injury was evaluated. In result, men in the moderate- and high-fatigue groups, after adjusting for age, smoking and drinking habits, chronic diseases, and occupational factors such as size of company industrial classification and type of work (shift or non-shift), adjusted ORs for hospital treatment due to occupational injury were 1.76 (95% confidence interval [CI]: 1.39-2.24) and 2.61 (95% CI:1.68-4.06), respectively. Among men in the medium- and high-fatigue groups, the adjusted ORs for absence due to occupational injury were 2.06 (95% CI: 1.52-2.80) and 3.65 (95% CI: 2.20-6.05), respectively. No significant association was observed between fatigue and occupational injury in women. CONCLUSIONS: Male workers with high fatigue levels have a higher risk of experiencing work injuries. This study suggests that active intervention be considered to prevent injuries in workers with high scores on workplace fatigue evaluation scales.

Association between nicotine dependency with occupational injury in Korean men.

BACKGROUND: The relationship between smoking status or second-hand smoking and occupational injuries has been the subject of considerable study, but few have studied the relationship between nicotine dependence and occupational injuries. The objective of this study was to investigate the relationship between nicotine dependence and occupational injury among employees at a range of Korean companies. METHODS: Initially, the personal and occupational characteristics and nicotine dependences of workers were measured, and 12 months later a survey was used to determine whether subjects had experienced any occupational injury. This study was conducted in several workplaces on 6,893 male workers in manufacturing and service industries that received health screening at Inha University Hospital in Incheon. RESULTS: The adjusted odds ratios (ORs) of occupational injury in the low, moderate, and high nicotine dependence groups were 1.38 (95% confidence interval [CI]: 1.04-1.84), 1.52 (95% CI: 1.10-2.10), and 1.71 (95% CI: 0.92-3.19), respectively. For smokers only, adjusted ORs tended to increase linearly (p for trend < 0.05). When only smokers were included, analysis of continuous FTND (Fagerstrom Test of Nicotine Dependence) scores showed that adjusted OR increased by 1.10 (95% CI: 1.03-1.19) per FTND point. After stratifying the data by working type and working hours per week, the non-shift work group maintained this relationship (OR: 1.13, 95% CI: 1.04-1.24) and OR was higher in the group that works more than 60 hours per week with FTND score as a continuous variable (OR: 1.24, 95% CI: 1.07-1.44). CONCLUSIONS: The study shows nicotine dependency might affect occupational injury. From a short-term perspective, addressing worker's nicotine dependence by giving an adequate break time or smoking area might reduce work-related injuries.

Structure-Based Exploration of Selectivity for ATM Inhibitors in Huntington's Disease.

Our group has recently shown that brain-penetrant ataxia telangiectasia-mutated (ATM) kinase inhibitors may have potential as novel therapeutics for the treatment of Huntington's disease (HD). However, the previously described pyranone-thioxanthenes (e.g., 4) failed to afford selectivity over a vacuolar protein sorting 34 (Vps34) kinase, an important kinase involved with autophagy. Given that impaired autophagy has been proposed as a pathogenic mechanism of neurodegenerative diseases such as HD, achieving selectivity over Vps34 became an important objective for our program. Here, we report the successful selectivity optimization of ATM over Vps34 by using X-ray crystal structures of a Vps34-ATM protein chimera where the Vps34 ATP-binding site was mutated to approximate that of an ATM kinase. The morpholino-pyridone and morpholino-pyrimidinone series that resulted as a consequence of this selectivity optimization process have high ATM potency and good oral bioavailability and have lower molecular weight, reduced lipophilicity, higher aqueous solubility, and greater synthetic tractability compared to the pyranone-thioxanthenes.

Locus-wide identification of Egr2/Krox20 regulatory targets in myelin genes.

Myelination of peripheral nerves by Schwann cells depends upon a gene regulatory network controlled by early growth response Egr2/Krox20, which is specifically required for Schwann cells to initiate and maintain myelination. To elucidate the mechanism by which Egr2 regulates gene expression during myelination, we have performed chromatin immunoprecipitation analysis on myelinating rat sciatic nerve in vivo. The resulting samples were applied to a tiled microarray consisting of a broad spectrum of genes that are activated or repressed in Egr2-deficient mice. The results show extensive binding within myelin-associated genes, as well as some genes that become repressed in myelinating Schwann cells. Many of the Egr2 peaks coincide with regions of open chromatin, which is a marker of enhancer regions. In addition, further analysis showed that there is substantial colocalization of Egr2 binding with Sox10, a transcription factor required for Schwann cell specification and other stages of Schwann cell development. Finally, we have found that Egr2 binds to promoters of several lipid biosynthetic genes, which is consistent with their dramatic up-regulation during the formation of lipid-rich myelin. Overall, this analysis provides a locus-wide profile of Egr2 binding patterns in major myelin-associated genes using myelinating peripheral nerve.

The relationship between precarious employment and subjective well-being in Korean wage workers through the Cantril ladder Scale.

BACKGROUND: The global labor market is moving towards increasing job instability. Relatively few studies have examined the relationship between precarious employment and subjective well-being using quantitative scales. We evaluated the association between wage workers' employment status and their subjective well-being through the Cantril ladder scale using Korean Welfare Panel Survey data (KOWEPS). METHODS: This study used KOWEPS data. A total of 4,423 wage workers were divided into permanently employed workers, temporarily employed workers and daily employed workers. The relationship between precarious employment and subjective well-being was analyzed by multiple linear regression adjusted for potential confounding factors. RESULTS: The more unstable the employment status, the lower the subjective well-being, which can be expressed by the Cantril ladder scale. The mean score of both temporarily employed and daily employed workers were statistically significantly lower (B = -0.454, p < 0.001; B = -0.994, p < 0.001, respectively) than permanently employed workers. This appeared to be the same when occupational and sociodemographic factors were adjusted (B = -0.153, p = 0.002 for temporarily employed, B = -0.610, p < 0.001 for daily employed). CONCLUSIONS: The more unstable the employment status, the lower the subjective well-being score according to the Cantril ladder scale.

Longitudinal associations between occupational stress and depressive symptoms.

BACKGROUND: Most of the studies that have examined the association between the sub-factors of occupational stress and depressive symptoms have used cross-sectional data. However, our study has longitudinally measured the occupational stress and depressive symptoms of Korean workers of a semiconductor manufacturing company across six years to intending to investigate the associations between the sub-factors of occupational stress and depressive symptoms using longitudinal data. METHODS: Data collected from the workers of a semiconductor manufacturing company. Out of 1,013 recruited workers, 405 (40.0%) completed the survey questionnaires at 3 and 6-year follow-ups. Occupational stress was measured using a shorter version of the Korean Occupational Stress Scale (KOSS), whereas depressive symptoms were assessed using the Korean version of the Center for Epidemiological Studies-Depressive Symptoms Scale (CES-D). The data of male and female participants independently analyzed. Longitudinal associations were analyzed using panel data analysis with fixed effects. RESULTS: In panel data analysis with fixed effects, job insecurity (B = 0.048, p-value = 0.004) was associated with depressive symptoms among male workers. In female workers, inadequate social support (B = 0.080, p-value < 0.001), job insecurity (B = 0.039, p-value = 0.004), lack of reward (B = 0.059, p-value = 0.004) and discomfort in occupational climate (B = 0.074, p-value < 0.001) were associated with depressive symptoms among female workers. CONCLUSIONS: Temporal changes in the sub-factors of occupational stress were associated with changes in depressive symptoms within the same period. There was a gender difference in occupational stress sub-factors related to depressive symptoms.

IgG4-Related Disease with Esophageal Involvement.

We report the case of a 56-year-old man who presented with dysphagia and weight loss. An esophagoduodenoscopy revealed a severe esophageal stricture in the distal esophagus. After surgical resection, the final pathologic analysis revealed that the tumor was comprised of benign-appearing fibroinflammatory cells with an increase and predominance of IgG4-positive plasma cells. He did not, however, have any other symptoms indicative of systemic autoimmune disease or connective tissue disorders. Histologically, abundant infiltration of IgG4-positive plasma cells and lymphocytes was observed. The patient was diagnosed with IgG4-related disease, definitive, with esophageal involvement.

Early Colon Cancer Recurring as Liver Metastasis without Local Recurrence Three Years after Complete Endoscopic Mucosal Resection.

Early colon cancer is defined as colon cancer that invades mucosal or submucosal layer regardless of lymph node invasion. Endoscopic mucosal resection can effectively remove early colon cancer which has no lymph node metastasis. Especially, pedunculated polyp has higher complete resection rate and lower recurrence rate that rarely needs additional surgical treatment than sessile polyp. Hence, it is common to follow up without additional treatment after complete resection of pedunculated polyp. We report a case of early colon cancer recurring as liver metastasis 3 years after complete endoscopic mucosal resection.

Relationship between occupational sunlight exposure and the incidence of renal cancer.

BACKGROUND: The risk factors for renal cancer include smoking, obesity, hypertension, and exposure to trichloroethylene. Recent studies have shown that low sunlight exposure increases the risk of developing a range of cancers, including renal cancer. Given that most of the daytime is spent at work, a lack of occupational sunlight exposure can be a risk factor for renal cancer. Therefore, this study examined the relationship between occupational sunlight exposure and the incidence of renal cancer. METHODS: This was a university hospital-based case-control study on renal cancer. Of the 706 newly diagnosed patients with renal cell carcinoma (RCC), 633 cases were selected; 73 who had no occupational history were excluded. In addition, 633 controls were selected from the general population after 1:1 matching with respect to sex, age (within 5 years), and residential area (constituency-level). Information on sunlight exposure by the occupational group was referred to data from France. To estimate the association between occupational sunlight exposure and the RCC risk, the odds ratios (ORs) were calculated using conditional logistic regression analysis. RESULTS: Sunlight exposure was divided into quartiles and the risk of RCC was analyzed. The adjusted OR of RCC (OR: 0.664, 95% confidence interval: 0.449-0.983) was significantly lower for the Q4 group than Q1 group but the Q2 and Q3 groups did not show significant results. The risk of RCC tended to decrease with increasing exposure to sunlight (p for trend < 0.028). CONCLUSIONS: Higher occupational sunlight exposure reduces the risk of RCC.

Optimization of Potent and Selective Ataxia Telangiectasia-Mutated Inhibitors Suitable for a Proof-of-Concept Study in Huntington's Disease Models.

Genetic and pharmacological evidence indicates that the reduction of ataxia telangiectasia-mutated (ATM) kinase activity can ameliorate mutant huntingtin (mHTT) toxicity in cellular and animal models of Huntington's disease (HD), suggesting that selective inhibition of ATM could provide a novel clinical intervention to treat HD. Here, we describe the development and characterization of ATM inhibitor molecules to enable in vivo proof-of-concept studies in HD animal models. Starting from previously reported ATM inhibitors, we aimed with few modifications to increase brain exposure by decreasing P-glycoprotein liability while maintaining potency and selectivity. Here, we report brain-penetrant ATM inhibitors that have robust pharmacodynamic (PD) effects consistent with ATM kinase inhibition in the mouse brain and an understandable pharmacokinetic/PD (PK/PD) relationship. Compound 17 engages ATM kinase and shows robust dose-dependent inhibition of X-ray irradiation-induced KAP1 phosphorylation in the mouse brain. Furthermore, compound 17 protects against mHTT (Q73)-induced cytotoxicity in a cortical-striatal cell model of HD.

Differential regulation of NAB corepressor genes in Schwann cells.

BACKGROUND: Myelination of peripheral nerves by Schwann cells requires not only the Egr2/Krox-20 transactivator, but also the NGFI-A/Egr-binding (NAB) corepressors, which modulate activity of Egr2. Previous work has shown that axon-dependent expression of Egr2 is mediated by neuregulin stimulation, and NAB corepressors are co-regulated with Egr2 expression in peripheral nerve development. NAB corepressors have also been implicated in macrophage development, cardiac hypertrophy, prostate carcinogenesis, and feedback regulation involved in hindbrain development. RESULTS: To test the mechanism of NAB regulation in Schwann cells, transfection assays revealed that both Nab1 and Nab2 promoters are activated by Egr2 expression. Furthermore, direct binding of Egr2 at these promoters was demonstrated in vivo by chromatin immunoprecipitation analysis of myelinating sciatic nerve, and binding of Egr2 to the Nab2 promoter was stimulated by neuregulin in primary Schwann cells. Although Egr2 expression activates the Nab2 promoter more highly than Nab1, we surprisingly found that only Nab1 - but not Nab2 - expression levels were reduced in sciatic nerve from Egr2 null mice. Analysis of the Nab2 promoter showed that it is also activated by ETS proteins (Ets2 and Etv1/ER81) and is bound by Ets2 in vivo. CONCLUSION: Overall, these results indicate that induction of Nab2 expression in Schwann cells involves not only Egr2, but also ETS proteins that are activated by neuregulin stimulation. Although Nab1 and Nab2 play partially redundant roles, regulation of Nab2 expression by ETS factors explains several observations regarding regulation of NAB genes. Finally, these data suggest that NAB proteins are not only feedback inhibitors of Egr2, but rather that co-induction of Egr2 and NAB genes is involved in forming an Egr2/NAB complex that is crucial for regulation of gene expression.

Comparison of remifentanil with dexmedetomidine for monitored anaesthesia care in elderly patients during vertebroplasty and kyphoplasty.

OBJECTIVES: This clinical trial is registered at ClinicalTrials.gov. (NCT02476981)This randomized, prospective double-blind study compared remifentanil with dexmedetomidine for monitored anaesthesia care during minimally invasive corrections of vertebral compression fractures (vertebroplasty or kyphoplasty). METHODS: Patients > 65 years of age with American Society of Anesthesiologists (ASA) classification I-III, scheduled for vertebroplasty or kyphoplasty under monitored anaesthesia care, received remifentanil (i.v. infusion 1-5 µg/kg/h) or dexmedetomidine (loading dose 0.3-0.4 µg/kg followed by i.v. infusion 0.2-1 µg/kg/h) to maintain observer's assessment of alertness/sedation (OAA/S) scale <4 during the procedure. RESULTS: There were no statistically significant differences in demographic data between the remifentanil (n = 37) and dexmedetomidine groups (n = 38). Patients on dexmedetomidine experienced lower mean arterial pressure (MAP) and heart rate (HR), and higher SpO2 values, than patients on remifentanil. Compared with dexmedetomidine, remifentanil produced more respiratory depression, oxygen desaturation, and reduced the need for additional intraoperative opioids. There were no significant between-group differences in terms of recovery time, investigators' satisfaction scores, or patients' overall pain experiences. CONCLUSIONS: During monitored anaesthesia care, dexmedetomidine provides less respiratory depression, lower MAP and HR, but also less analgesic effect than remifentanil in elderly patients undergoing vertebroplasty or kyphoplasty.

Genome editing-enabled HTS assays expand drug target pathways for Charcot-Marie-tooth disease.

Copy number variation resulting in excess PMP22 protein causes the peripheral neuropathy Charcot-Marie-Tooth disease, type 1A. To broadly interrogate chemically sensitive transcriptional pathways controlling PMP22 protein levels, we used the targeting precision of TALEN-mediated genome editing to embed reporters within the genetic locus harboring the Peripheral Myelin Protein 22 (Pmp22) gene. Using a Schwann cell line with constitutively high endogenous levels of Pmp22, we obtained allelic insertion of secreted bioluminescent reporters with sufficient signal to enable a 1536-well assay. Our findings from the quantitative high-throughput screening (qHTS) of several thousand drugs and clinically investigated compounds using this assay design both overlapped and expanded results from a previous assay using a randomly inserted reporter gene controlled by a single regulatory element of the Pmp22 gene. A key difference was the identification of a kinase-controlled inhibitory pathway of Pmp22 transcription revealed by the activity of the Protein kinase C (PKC)-modulator bryostatin.

Identification of drug modulators targeting gene-dosage disease CMT1A.

The structural integrity of myelin formed by Schwann cells in the peripheral nervous system (PNS) is required for proper nerve conduction and is dependent on adequate expression of myelin genes including peripheral myelin protein 22 (PMP22). Consequently, excess PMP22 resulting from its genetic duplication and overexpression has been directly associated with the peripheral neuropathy called Charcot-Marie-Tooth disease type 1A (CMT1A), the most prevalent type of CMT. Here, in an attempt to identify transcriptional inhibitors with therapeutic value toward CMT1A, we developed a cross-validating pair of orthogonal reporter assays, firefly luciferase (FLuc) and ß-lactamase (ßLac), capable of recapitulating PMP22 expression, utilizing the intronic regulatory element of the human PMP22 gene. Each compound from a collection of approximately 3,000 approved drugs was tested at multiple titration points to achieve a pharmacological end point in a 1536-well plate quantitative high-throughput screen (qHTS) format. In conjunction with an independent counter-screen for cytotoxicity, the design of our orthogonal screen platform effectively contributed to selection and prioritization of active compounds, among which three drugs (fenretinide, olvanil, and bortezomib) exhibited marked reduction of endogenous Pmp22 mRNA and protein. Overall, the findings of this study provide a strategic approach to assay development for gene-dosage diseases such as CMT1A.

Induction of myelin protein zero by early growth response 2 through upstream and intragenic elements.

The Mpz (myelin protein zero) gene codes for the principal component of myelin in the peripheral nervous system, and mutations in this gene cause human peripheral myelinopathies. Expression of the Mpz gene is controlled by two major transactivators that coordinate Schwann cell development: Egr2/Krox20 and Sox10. Our in vivo ChIP-chip analysis in myelinating peripheral nerve identified major sites of Egr2 interaction within the first intron of the Mpz gene and approximately 5 kb upstream of the transcription start site. In addition, the sites of Egr2 binding display many of the hallmarks associated with enhancer elements. Interestingly, the upstream Egr2 binding sites lie proximal to the divergently transcribed succinate dehydrogenase C gene, but Sdhc expression was not affected by the massive induction of Mpz mediated by Egr2. Mpz induction was greatly enhanced in the presence of the Egr2 binding sites, and removal of them markedly diminished transgenic expression of a construct derived from the Mpz locus. Sox10 was also found to be associated with the upstream region, and its binding was required for Egr2-mediated activation in this distal regulatory region. Our findings highlight that peripheral nerve-specific expression of Mpz is primarily regulated by both upstream and intron-associated regulatory elements. Overall, these results provide a locus-wide analysis of the role and activity of Egr2 in regulation of the Mpz gene within its native chromosomal context.

Active gene repression by the Egr2.NAB complex during peripheral nerve myelination.

The Egr2/Krox20 transactivator is required for activation of many myelin-associated genes during peripheral nerve myelination by Schwann cells. However, recent work has indicated that Egr2 not only activates genes required for peripheral nerve myelination but may also be involved in gene repression. The NAB (NGFI-A/Egr-binding) corepressors interact with Egr2 and are required for proper coordination of myelin formation. Therefore, NAB proteins could mediate repression of some Egr2 target genes, although direct repression by Egr2 or NAB proteins during myelination has not been demonstrated. To define the physiological role of NAB corepression in gene repression by Egr2, we tested whether the Egr2.NAB complex directly repressed specific target genes. A screen for NAB-regulated genes identified several (including Id2, Id4, and Rad) that declined during the course of peripheral nerve myelination. In vivo chromatin immunoprecipitation analysis of the myelinating sciatic nerve was used to show developmental association of both Egr2 and NAB2 on the Id2, Id4, and Rad promoters as they were repressed during the myelination process. In addition, NAB2 represses transcription by interaction with the chromodomain helicase DNA-binding protein 4 (CHD4) subunit of the nucleosome remodeling and deacetylase chromatin remodeling complex, and we demonstrate that CHD4 occupies NAB-repressed promoters in a developmentally regulated manner in vivo. These results illustrate a novel aspect of genetic regulation of peripheral nerve myelination by showing that Egr2 directly represses genes during myelination in conjunction with NAB corepressors. Furthermore, repression of Id2 was found to augment activation of Mpz (myelin protein zero) expression.

Interactions of Sox10 and Egr2 in myelin gene regulation.

Myelination in the PNS is accompanied by a large induction of the myelin protein zero (Mpz) gene to produce the most abundant component in peripheral myelin. Analyses of knockout mice have shown that the EGR2/Krox20 and SOX10 transcription factors are required for Mpz expression. Our recent work has shown that the dominant EGR2 mutations associated with human peripheral neuropathies cause disruption of EGR2/SOX10 synergy at specific sites, including a conserved enhancer element in the first intron of the Mpz gene. Further investigation of Egr2/Sox10 interactions reveals that activation of the Mpz intron element by Egr2 requires both Sox10-binding sites. In addition, both Egr1 and Egr3 cooperate with Sox10 to activate this element, which indicates that this capacity is conserved among Egr family members. Finally, a conserved composite structure of Egr2/Sox10-binding sites in the genes encoding Mpz, myelin-associated glycoprotein and myelin basic protein genes was used to screen for similar modules in other myelin genes, revealing a potential regulatory element in the periaxin gene. Overall, these results elucidate a working model for developmental regulation of Mpz expression, several facets of which extend to regulation of other peripheral myelin genes.

Direct regulation of myelin protein zero expression by the Egr2 transactivator.

During myelination of the peripheral nervous system, the myelin protein zero (Mpz) gene is induced to produce the most abundant protein component (P(0)) of mature myelin. Although the basal embryonic expression of Mpz in Schwann cells has been attributed to regulation by Sox10, the molecular mechanism for the profound up-regulation of this gene during myelination has not been established. In this study, we have identified a highly conserved element within the first intron of the Mpz gene, which contains binding sites for the early growth response 2 (Egr2/Krox20) transcription factor, a critical regulator of peripheral nerve myelination. Egr2 can transactivate the intron element, and the induction is blocked by two known repressors of Egr2 activity. Using chromatin immunoprecipitation assays, we find that Egr2 binds in vivo to the intron element, but not to the Mpz promoter. Known inducers of Mpz expression such as forskolin and insulin-like growth factor-1 also activate the element in an Egr2-dependent manner. In addition, we found that Egr2 can act synergistically with Sox10 to activate this intron element, suggesting a model in which cooperative interactions between Egr2 and Sox10 mediate a large increase in Mpz expression to the high levels found in myelinating Schwann cells.