The Experts below are selected from a list of 101850 Experts worldwide ranked by ideXlab platform
Graeme J Stewart - One of the best experts on this subject based on the ideXlab platform.
-
Interleukin 7 Receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon beta
Journal of Interferon and Cytokine Research, 2010Co-Authors: Edwin Hoe, Robert Heard, Graeme J Stewart, Fiona C. Mckay, Steven Schibeci, David R BoothAbstract:Interleukin 7 Receptor alpha chain (IL-7Rα) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Rα, and therefore reduced interference with Receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 × 10–10), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Rα proximal promoter contains response elements to interferon beta (IFN-β), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Rα is up-regulated in response to IFN-β in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P < 0.002, n = 10) and homozygotes (trend onl...
-
Interleukin 7 Receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon Beta.
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2010Co-Authors: Edwin Hoe, Robert Heard, Graeme J Stewart, Fiona C. Mckay, Steven Schibeci, David R BoothAbstract:Interleukin 7 Receptor alpha chain (IL-7Ralpha) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Ralpha, and therefore reduced interference with Receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 x 10(-10)), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Ralpha proximal promoter contains response elements to interferon beta (IFN-beta), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Ralpha is up-regulated in response to IFN-beta in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P < 0.002, n = 10) and homozygotes (trend only), and in CD4 + CD45RO + and CD4 + CD45RA + cells. In PBMCs, IL-7Ralpha cell surface protein (CD127) is lower in haplotype 4 carriers than non-carriers after incubation with IFN-beta (P < 0.003, n = 20). Response to IFN-beta includes viral protection and immune modulation, processes that could be pathogenically significant in MS. The haplotype-dependent variation in the regulation of IL-7Ralpha by IFN-beta may contribute to the genetic association of IL-7Ralpha with MS.
-
Interleukin 7 Receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon Beta.
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2010Co-Authors: Edwin Hoe, Robert Heard, Graeme J Stewart, Fiona C. Mckay, Steven Schibeci, David R BoothAbstract:Interleukin 7 Receptor alpha chain (IL-7Rα) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Rα, and therefore reduced interference with Receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 × 10–10), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Rα proximal promoter contains response elements to interferon beta (IFN-β), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Rα is up-regulated in response to IFN-β in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P
-
gene expression and genotyping studies implicate the Interleukin 7 Receptor in the pathogenesis of primary progressive multiple sclerosis
Journal of Molecular Medicine, 2005Co-Authors: David R Booth, Suzy Teutsch, Robert Heard, Ariel T Arthur, Christopher R Bye, Justin P Rubio, Patricia J Armati, J D Pollard, Graeme J StewartAbstract:Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing–remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P<10−4, χ2). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One Interleukin 7 Receptor (IL7R) promoter single nucleotide polymorphism (SNP), −504 C, was undertransmitted in PPMS trios (P=0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P=0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P<0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.
-
identification of 11 novel and common single nucleotide polymorphisms in the Interleukin 7 Receptor α gene and their associations with multiple sclerosis
European Journal of Human Genetics, 2003Co-Authors: Suzy Teutsch, David R Booth, Bruce Bennetts, Robert Heard, Graeme J StewartAbstract:Identification of 11 novel and common single nucleotide polymorphisms in the Interleukin-7 Receptor- α gene and their associations with multiple sclerosis
Sebastian Kummer - One of the best experts on this subject based on the ideXlab platform.
-
Interleukin-7 Receptor α-chain haplotypes differentially affect soluble IL-7 Receptor and IL-7 serum concentrations in children with type 1 diabetes.
Pediatric diabetes, 2018Co-Authors: Julia Seyfarth, Christian Lundtoft, Katharina Förtsch, Heinz Ahlert, Joachim Rosenbauer, Christina Baechle, Michael Roden, Reinhard W. Holl, Ertan Mayatepek, Sebastian KummerAbstract:Interleukin-7 Receptor α-chain (IL7RA) haplotypes are associated with susceptibility for development of autoimmune diseases, including type 1 diabetes (T1D). A protective IL7RA haplotype which causes lower soluble IL-7R (sIL-7R) serum levels is hypothesized to restrict IL-7-availability for self-reactive T cells. Functional mechanisms affected by a risk-associated IL7RA haplotype are unknown. We investigated the influence of IL7RA haplotypes (tagged by rs6897932T for the protective or by rs1494555G for the risk haplotype) on sIL-7R and IL-7 serum concentrations as well as disease manifestation of children with T1D (n = 259). Possible effects of differential IL-7 serum concentrations on IL-7-mediated in vitro T cell functions (i.e. IL-7R regulation and cytokine expression) were measured in a second study group of children with T1D (n = 42). We detected lower sIL-7R serum concentrations in children with T1D carrying protective or risk haplotypes as compared to reference haplotypes. sIL-7R levels were lowest in T1D children with the protective haplotype and lower IL-7 serum levels were exclusively detected in this study group. We found no evidence for dependency between IL-7 and sIL-7R serum concentrations and no association with T1D manifestation. Neither IL-7 nor sIL-7R serum levels were associated with mIL-7R regulation or IL-7-promoted T cell cytokine expression. Children with T1D carrying autoimmunity risk- or protection-associated IL7RA haplotypes had both lower sIL-7R serum concentrations as compared to the reference haplotype, but only T1D children with the protective haplotype had lower IL-7 serum levels. Our results suggest additional functional mechanisms of autoimmunity-associated IL7RA variants independent from sIL-7R mediated regulation of IL-7 availability for T cells. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
-
Interleukin-7 Receptor α-chain haplotypes differentially affect soluble IL-7 Receptor and IL-7 serum concentrations in children with type 1 diabetes.
Pediatric diabetes, 2018Co-Authors: Julia Seyfarth, Christian Lundtoft, Katharina Förtsch, Heinz Ahlert, Joachim Rosenbauer, Christina Baechle, Michael Roden, Reinhard W. Holl, Ertan Mayatepek, Sebastian KummerAbstract:Background Interleukin-7 Receptor α-chain (IL7RA) haplotypes are associated with susceptibility for development of autoimmune diseases, including type 1 diabetes (T1D). A protective IL7RA haplotype which causes lower soluble IL-7R (sIL-7R) serum levels is hypothesized to restrict IL-7-availability for self-reactive T cells. Functional mechanisms affected by a risk-associated IL7RA haplotype are unknown. Methods We investigated the influence of IL7RA haplotypes (tagged by rs6897932T for the protective or by rs1494555G for the risk haplotype) on sIL-7R and IL-7 serum concentrations as well as disease manifestation of children with T1D (n = 259). Possible effects of differential IL-7 serum concentrations on IL-7-mediated in vitro T cell functions (i.e. IL-7R regulation and cytokine expression) were measured in a second study group of children with T1D (n = 42). Results We detected lower sIL-7R serum concentrations in children with T1D carrying protective or risk haplotypes as compared to reference haplotypes. sIL-7R levels were lowest in T1D children with the protective haplotype and lower IL-7 serum levels were exclusively detected in this study group. We found no evidence for dependency between IL-7 and sIL-7R serum concentrations and no association with T1D manifestation. Neither IL-7 nor sIL-7R serum levels were associated with mIL-7R regulation or IL-7-promoted T cell cytokine expression. Conclusions Children with T1D carrying autoimmunity risk- or protection-associated IL7RA haplotypes had both lower sIL-7R serum concentrations as compared to the reference haplotype, but only T1D children with the protective haplotype had lower IL-7 serum levels. Our results suggest additional functional mechanisms of autoimmunity-associated IL7RA variants independent from sIL-7R mediated regulation of IL-7 availability for T cells.
David R Booth - One of the best experts on this subject based on the ideXlab platform.
-
Interleukin 7 Receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon beta
Journal of Interferon and Cytokine Research, 2010Co-Authors: Edwin Hoe, Robert Heard, Graeme J Stewart, Fiona C. Mckay, Steven Schibeci, David R BoothAbstract:Interleukin 7 Receptor alpha chain (IL-7Rα) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Rα, and therefore reduced interference with Receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 × 10–10), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Rα proximal promoter contains response elements to interferon beta (IFN-β), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Rα is up-regulated in response to IFN-β in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P < 0.002, n = 10) and homozygotes (trend onl...
-
Interleukin 7 Receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon Beta.
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2010Co-Authors: Edwin Hoe, Robert Heard, Graeme J Stewart, Fiona C. Mckay, Steven Schibeci, David R BoothAbstract:Interleukin 7 Receptor alpha chain (IL-7Ralpha) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Ralpha, and therefore reduced interference with Receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 x 10(-10)), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Ralpha proximal promoter contains response elements to interferon beta (IFN-beta), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Ralpha is up-regulated in response to IFN-beta in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P < 0.002, n = 10) and homozygotes (trend only), and in CD4 + CD45RO + and CD4 + CD45RA + cells. In PBMCs, IL-7Ralpha cell surface protein (CD127) is lower in haplotype 4 carriers than non-carriers after incubation with IFN-beta (P < 0.003, n = 20). Response to IFN-beta includes viral protection and immune modulation, processes that could be pathogenically significant in MS. The haplotype-dependent variation in the regulation of IL-7Ralpha by IFN-beta may contribute to the genetic association of IL-7Ralpha with MS.
-
Interleukin 7 Receptor alpha chain haplotypes vary in their influence on multiple sclerosis susceptibility and response to interferon Beta.
Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research, 2010Co-Authors: Edwin Hoe, Robert Heard, Graeme J Stewart, Fiona C. Mckay, Steven Schibeci, David R BoothAbstract:Interleukin 7 Receptor alpha chain (IL-7Rα) has recently been confirmed as the first non-HLA gene definitively associated with multiple sclerosis (MS). The protective haplotype (haplotype 2) has reduced splicing of exon 6, reduced production of soluble IL-7Rα, and therefore reduced interference with Receptor binding to its ligands, IL-7, and thymic stromal lymphopoietin (TSLP). From a meta-analysis on 3,376 MS patients, 4,143 controls, and 1,333 trio families, although the most significant association is still seen with haplotype 2 (P = 7 × 10–10), the highest odds ratio is seen for haplotype 4 homozygotes (OR = 1.35, P = 0.001). The IL-7Rα proximal promoter contains response elements to interferon beta (IFN-β), the most commonly used immunomodulatory drug in MS. We demonstrate that IL-7Rα is up-regulated in response to IFN-β in vitro for haplotypes 1 and 2, but not 4. This difference can be seen in peripheral blood mononuclear cells (PBMC) from heterozygotes (P
-
gene expression and genotyping studies implicate the Interleukin 7 Receptor in the pathogenesis of primary progressive multiple sclerosis
Journal of Molecular Medicine, 2005Co-Authors: David R Booth, Suzy Teutsch, Robert Heard, Ariel T Arthur, Christopher R Bye, Justin P Rubio, Patricia J Armati, J D Pollard, Graeme J StewartAbstract:Multiple sclerosis (MS) is an enigmatic disease of the central nervous system resulting in sclerotic plaques with the pathological hallmarks of demyelination and axonal damage, which can be directly or indirectly orchestrated by cells from the peripheral circulation. The majority of patients with MS follow a relapsing–remitting course in the early stages of the disease (RRMS) but most ultimately enter a secondary progressive phase (SPMS). About 10% of patients follow a primary progressive course from the onset (PPMS). We measured gene expression in whole blood of people with and without chronic progressive MS (CPMS), PPMS and SPMS, to discover genes which may be differentially expressed in peripheral blood in active disease, and so identify pathologically significant genes and pathways; and we investigated genetic differences in the promoters of dysregulated genes encoded in genomic regions associated with MS. If SPMS and PPMS were independently compared to the controls, there was little overlap in the set of most dysregulated genes. Ribosomal protein genes, whose expression is usually associated with cell proliferation and activation, were dramatically over-represented in the set of most down-regulated genes in PPMS compared to SPMS (P<10−4, χ2). The T cell proliferation gene IL7R (CD127) was also underexpressed in PPMS, but was up-regulated in SPMS compared to the controls. One Interleukin 7 Receptor (IL7R) promoter single nucleotide polymorphism (SNP), −504 C, was undertransmitted in PPMS trios (P=0.05, TDT), and carriers of this allele were under-represented in PPMS cases from two independent patient cohorts (combined P=0.006, FE). The four known IL7R promoter haplotypes were shown to have similar expression levels in healthy controls, but not in CPMS (P<0.01, t test). These data support the hypothesis that PPMS has significant pathogenetic differences from SPMS, and that IL7R may be a useful therapeutic target in PPMS.
-
identification of 11 novel and common single nucleotide polymorphisms in the Interleukin 7 Receptor α gene and their associations with multiple sclerosis
European Journal of Human Genetics, 2003Co-Authors: Suzy Teutsch, David R Booth, Bruce Bennetts, Robert Heard, Graeme J StewartAbstract:Identification of 11 novel and common single nucleotide polymorphisms in the Interleukin-7 Receptor- α gene and their associations with multiple sclerosis
Bernard Lauwerys - One of the best experts on this subject based on the ideXlab platform.
-
Serum soluble Interleukin 7 Receptor is strongly associated with lupus nephritis in patients with systemic lupus erythematosus
Annals of the rheumatic diseases, 2012Co-Authors: Valérie Badot, Joel A G Van Roon, Remco K M A C Luijten, G Depresseux, Selda Aydin, Benoît Van Den Eynde, Frédéric Houssiau, Bernard LauwerysAbstract:BACKGROUND: The soluble form of the Interleukin 7 Receptor (sIL-7R) is produced by fibroblasts after stimulation with proinflammatory cytokines. Increased sIL-7R serum and synovial fluid levels were recently demonstrated in patients with rheumatoid arthritis. OBJECTIVES: To investigate whether sIL-7R production is dysregulated in systemic lupus erythematosus (SLE), and whether this correlates with disease activity. METHODS: Serum and urine sIL-7R concentrations were measured by ELISA, and sIL-7R quantitative PCR (qPCR) studies were performed in peripheral blood mononuclear cells (PBMCs). IL-7R, tumour necrosis factor α (TNFα), IL-1β and IL-17 immunostainings were performed on kidney sections. RESULTS: sIL-7R concentrations were significantly higher in SLE sera than in controls, and correlated with SLE Disease Activity Index (SLEDAI) scores. Accordingly, serum sIL-7R levels were strongly raised in patients with nephritis. Moreover in patients with lupus nephritis, serum sIL-7R decreased upon treatment. sIL-7R gene expression in PBMCs was similar in patients with lupus nephritis and controls. By contrast, abundant perivascular IL-7R expression was seen in SLE kidney biopsy specimens, which was associated with expression of TNFα in the surrounding tissue. CONCLUSIONS: Our data indicate that sIL-7R is a marker of SLE disease activity, especially nephritis. In contrast to conventional disease activity markers, sIL-7R is not produced by immune cells, but might instead reflect activation of tissue cells in the target organ.
-
Rheumatoid arthritis synovial fibroblasts produce a soluble form of the Interleukin-7 Receptor in response to pro-inflammatory cytokines.
Journal of cellular and molecular medicine, 2011Co-Authors: Valérie Badot, Benoît Van Den Eynde, Frédéric Houssiau, Patrick Durez, A. Nzeusseu-toukap, Bernard LauwerysAbstract:We previously demonstrated that baseline synovial overexpression of the Interleukin-7 Receptor α-chain (IL-7R) is associated with poor response to tumour necrosis factor (TNF) blockade in rheumatoid arthritis (RA). We found that IL-7R gene expression is induced in fibroblast-like synovial cells (FLS) by the addition of TNF-α, IL-1β and combinations of TNF-α+ IL-1β or TNF-α+ IL-17, thereby suggesting that these cytokines play a role in the resistance to TNF blockade in RA. Because FLS and CD4 T cells also produce a soluble form of IL-7R (sIL-7R), resulting from an alternative splicing of the full-length transcript, we wondered whether expression of sIL-7R is similarly regulated by pro-inflammatory cytokines. We also investigated whether sIL-7R is detectable in the serum of RA patients and associated with response to TNF blockade. RA FLS were cultured in the presence of pro-inflammatory cytokines and sIL-7R concentrations were measured in culture supernatants. Similarly, sIL-7R titres were measured in sera obtained from healthy individuals, early untreated RA patients with active disease and disease-modifying anti-rheumatic drug (DMARD)-resistant RA patients prior to initiation of TNF-blockade. Baseline serum sIL-7R titres were correlated with validated clinical measurements of disease activity. We found that exposure of RA FLS to pro-inflammatory cytokines (TNF-α, IL-1β and combinations of TNF-α and IL-1β or TNF-α and IL-17) induces sIL-7R secretion. Activated CD4 T cells also produce sIL-7R. sIL-7R serum levels are higher in RA patients as compared to controls. In DMARD-resistant patients, high sIL-7R serum concentrations are strongly associated with poor response to TNF-blockade. In conclusion, sIL-7R is induced by pro-inflammatory cytokines in RA FLS. sIL-7R could qualify as a new biomarker of response to therapy in RA.
Jianlin Cui - One of the best experts on this subject based on the ideXlab platform.
-
knockout of zebrafish Interleukin 7 Receptor il7r by the crispr cas9 system delays retinal neurodevelopment
Cell Death and Disease, 2018Co-Authors: Shi-jiao Cai, Yang Chen, Yue Shang, Jianlin CuiAbstract:Interleukin 7 Receptor (il7r), a transmembrane Receptor, belongs to the type I cytokine Receptor family. Il7r is involved in the pathogenesis of neurodegenerative disorders, such as multiple sclerosis. Targeted knockdown of il7r leads to delayed myelination, highlighting the potential role of il7r in the development of the nervous system. Zebrafish is an ideal model for the study of neurogenesis; moreover, the il7r gene is highly conserved between zebrafish and human. The aim of the present study was to investigate the novel function of il7r in neurogenesis. First, an il7r -/- homozygous mutant line was generated by clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) technology. Second, the gross development of il7r-/- mutants revealed remarkably smaller eyes and delayed retinal neurodifferentiation. Third, microarray analysis revealed that genes associated with the phototransduction signalling pathway were strongly down-regulated in il7r -/- mutants. Finally, the results from behavioural tests indicated that visual function was impaired in il7r -/- mutant larvae. Overall, our data demonstrate that a lack of il7r retards the development of the retina. Thus, il7r is an essential molecule for maintaining normal retinal development in zebrafish.
-
Knockout of zebrafish Interleukin 7 Receptor (IL7R) by the CRISPR/Cas9 system delays retinal neurodevelopment.
Cell death & disease, 2018Co-Authors: Shi-jiao Cai, Yang Chen, Yue Shang, Jianlin CuiAbstract:Interleukin 7 Receptor (il7r), a transmembrane Receptor, belongs to the type I cytokine Receptor family. Il7r is involved in the pathogenesis of neurodegenerative disorders, such as multiple sclerosis. Targeted knockdown of il7r leads to delayed myelination, highlighting the potential role of il7r in the development of the nervous system. Zebrafish is an ideal model for the study of neurogenesis; moreover, the il7r gene is highly conserved between zebrafish and human. The aim of the present study was to investigate the novel function of il7r in neurogenesis. First, an il7r -/- homozygous mutant line was generated by clustered regularly interspaced short palindromic repeats (CRISPR)-associated 9 (CRISPR/Cas9) technology. Second, the gross development of il7r-/- mutants revealed remarkably smaller eyes and delayed retinal neurodifferentiation. Third, microarray analysis revealed that genes associated with the phototransduction signalling pathway were strongly down-regulated in il7r -/- mutants. Finally, the results from behavioural tests indicated that visual function was impaired in il7r -/- mutant larvae. Overall, our data demonstrate that a lack of il7r retards the development of the retina. Thus, il7r is an essential molecule for maintaining normal retinal development in zebrafish.
-
Down-regulation of Interleukin 7 Receptor (IL-7R) contributes to central nervous system demyelination.
Oncotarget, 2017Co-Authors: Xudan Lei, Shi-jiao Cai, Yang Chen, Jianlin Cui, Yajie WangAbstract:// Xudan Lei 1 , Shijiao Cai 1 , Yang Chen 1 , Jianlin Cui 1 , Yajie Wang 1 , Zongjin Li 1 , Yuhao Li 1 1 Key Laboratory of Tumor Microenvironment and Neurovascular Regulation, Nankai University School of Medicine, Tianjin 300071, China Correspondence to: Yuhao Li, email: liyuhao@nankai.edu.cn Keywords: Interleukin 7 Receptor (IL-7R), demyelination, myelin basic protein, myelination, zebrafish Received: November 08, 2016 Accepted: February 27, 2017 Published: March 10, 2017 ABSTRACT Interleukin 7 Receptor (IL-7R) has been associated with the pathogenesis of multiple sclerosis (MS), though the mechanisms are not clear. Because myelin expression is highly conserved between zebrafish and mammals, zebrafish have become an ideal model for studying demyelination. We used a transgenic (Tg; mbp:nfsB-egfp ) zebrafish line in which oligodendrocytes expressed green fluorescent protein (GFP) from the larval stage to adulthood. Exposing adult transgenic zebrafish to metronidazole induced demyelination that resembled the morphological changes associated with the early stages of MS. The metronidazole-induced demyelination was confirmed by magnetic resonance imaging (MRI) for the first time. Microarray analysis revealed down-regulation of IL-7R during demyelination. Targeted knockdown of IL-7R demonstrated that IL-7R is essential for myelination in embryonic and larval zebrafish. Moreover, IL-7R down-regulation induced signaling via the JAK/STAT pathway leading to apoptosis in oligodendrocytes. These findings contribute to our understanding of the role of IL-7R in demyelination, and provide a rationale for the development of IL-7R-based therapies for MS and other demyelinating diseases.