WT1 expression does not disrupt myogenic differentiation in C2C12 murine myoblasts or in human rhabdomyosarcoma

Tiffin, Nicki; Williams, Richard D.; Robertson, David; Hill, Suzanne; Shipley, Janet; Pritchard‐Jones, Kathy

doi:10.1016/s0014-4827(03)00131-9

Cited by 3 publications

(3 citation statements)

References 40 publications

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“…The literature on this is contradictory. One study described that overexpression of Wt1 in myoblast cells did indeed inhibit their differentiation ( Miyagawa et al, 1998 ), but a second study could not confirm this ( Tiffin et al, 2003 ). The data presented here clearly justifies more work on this.…”

Section: Discussionmentioning

confidence: 99%

Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1 mutants

Berry

Ozdemir

Aronow

et al. 2015

Disease Models &Amp; Mechanisms

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Wilms' tumours, paediatric kidney cancers, are the archetypal example of tumours caused through the disruption of normal development. The genetically best-defined subgroup of Wilms' tumours is the group caused by biallelic loss of the WT1 tumour suppressor gene. Here, we describe a developmental series of mouse models with conditional loss of Wt1 in different stages of nephron development before and after the mesenchymal-to-epithelial transition (MET). We demonstrate that Wt1 is essential for normal development at all kidney developmental stages under study. Comparison of genome-wide expression data from the mutant mouse models with human tumour material of mutant or wild-type WT1 datasets identified the stage of origin of human WT1-mutant tumours, and emphasizes fundamental differences between the two human tumour groups due to different developmental stages of origin.

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Section: Discussionmentioning

confidence: 99%

Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1 mutants

Berry

Ozdemir

Aronow

et al. 2015

Disease Models &Amp; Mechanisms

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“…The role of WT1 in regulating muscle cell lineage differentiation has been suggested in the development of primitive skeletal muscle in kidney with WT1 mutation (42) and the inhibition of myogenic differentiation by overexpression of WT1 in a murine myoblastic cell line (43). Although the latter evidence has been disputed by another study (44), the essential roles of WT1 in regeneration and repair of damaged hearts has been demonstrated (45)(46)(47). Reexpression of WT1 activated the progenitor cell populations in the adult heart after injury (46).…”

Section: Discussionmentioning

confidence: 99%

Methylation alterations of WT1 and homeobox genes in inflamed muscle biopsy samples from patients with untreated juvenile dermatomyositis suggest self‐renewal capacity

Wang¹,

Xie²,

Shrestha³

et al. 2012

Arthritis & Rheumatism

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Objective To determine the impact of methylation alteration in inflamed muscles from children with Juvenile Dermatomyositis (JDM) and other Idiopathic Inflammatory Myopathies (IIM). Methods MRI-directed diagnostic muscle biopsies (MBx) from 20 JDM children and 4 healthy controls were used for genome-wide DNA methylation profiling (IRB# 200813457). Bisulfite pyrosequencing confirmed methylation status in JDM and other IIM. Immunohistochemistry defined localization and expression levels of WT1. Results Comparison of genome-wide DNA methylation profiling between JDM and normal controls revealed 27 genes with significant methylation difference, enriched with transcription factors and cell cycle regulators, unrelated to duration of untreated disease. Six homeobox genes were among them: ALX4, HOXC11, HOXD3 and HOXD4 were hypomethylated; EMX2 and HOXB1 were hypermethylated. WT1 was significantly hypomethylated in JDM (Δβ = −0.41, p < 0.001). Bisulfite pyrosequencing verification in 56 JDM samples confirmed the methylation alterations of these genes. Similar methylation alterations were observed in Juvenile Polymyositis (JPM, n = 5) and other IIM (n = 9). Concordantly, WT1 protein was increased in JDM muscle, with average positive staining of 11.6%, but was undetectable in normal muscles (p < 0.05). Conclusions These results suggest that affected muscles of children with JDM and IIM have the capacity to repair, and that homeobox and WT1 genes are epigenetically marked to facilitate this repair process, potentially suggesting new avenues of therapeutic intervention.

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“…WT1 was suggested to be an inhibitor of myogenesis, as Wilms tumors, especially those with WT1 mutations, sometimes differentiate into primitive skeletal muscle [Schumacher et al, 1997]. Additionally, transfection of a murine myoblastic cell line with a Wt1 expression construct was found to inhibit myogenic differentiation [Miyagawa et al, 1998], although this could not be reproduced [Tiffin et al, 2003]. The deregulation of genes, which play a role in muscle development, in Wt1 -/-urogenital ridges would be in line with an inhibitory effect of WT1 on myogenesis.…”

Section: Differential Gene Expression Analysismentioning

confidence: 99%

WT1-Mediated Gene Regulation in Early Urogenital Ridge Development

Klattig

Sierig²,

Kruspe³

et al. 2007

Sex Dev

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The Wilms tumor protein WT1 is involved in the development of several organs, including the gonads. WT1 mutations in humans lead to syndromes associated with impaired sexual development and Wt1 knockout mice show regression of gonad anlagen. As a transcription factor, WT1 fulfills its function by regulating a set of target genes. With respect to gonad development only few in vivo WT1 targets, e.g. steroidogenic factor 1 (SF1) have been identified so far. To get a comprehensive view of WT1 targets in the gonad, we compared gene expression in urogenital ridges of wild-type and Wt1^–/– embryos. We found almost 150 genes differentially expressed higher than factor three, using microarray analysis. To confirm these results we performed quantitative real-time RT-PCR for many genes and observed a high degree of concordance between microarray and real-time RT-PCR results. Employing in situ hybridization we found ‘WT1 activated genes’ to be expressed in gonads, mesonephroi and coelomic epithelium – those parts of the urogenital ridge with Wt1 expression. Interestingly, many of the differentially expressed genes are known to show sex-specific expression at later time-points. These results provide a basis for investigation of developmental pathways in the urogenital ridge downstream of WT1 and for identification of new candidate genes involved in early urogenital ridge development. For example we provide a first potential target of WT1 in the coelomic epithelium – Muc16, and a gene regulated by the WT1 target SF1 – Gata4.

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WT1 expression does not disrupt myogenic differentiation in C2C12 murine myoblasts or in human rhabdomyosarcoma

Cited by 3 publications

References 40 publications

Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1 mutants

Deducing the stage of origin of Wilms' tumours from a developmental series of Wt1 mutants

Methylation alterations of WT1 and homeobox genes in inflamed muscle biopsy samples from patients with untreated juvenile dermatomyositis suggest self‐renewal capacity

WT1-Mediated Gene Regulation in Early Urogenital Ridge Development

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