title: Characterisation of multiple regulatory domains spanning the major transcriptional start site of the FUS gene, a candidate gene for motor neurone disease.
abstract: Fused-In-Sarcoma (FUS) is a candidate gene for neurological disorders including motor neurone disease and Parkinson׳s disease in addition to various types of cancer. Recently it has been reported that over expression of FUS causes motor neurone disease in mouse models hence mutations leading to changes in gene expression may contribute to the development of neurodegenerative disease. Genome evolutionary conservation was used to predict important cis-acting DNA regulators of the FUS gene promoter that direct transcription. The putative regulators identified were analysed in reporter gene assays in cells and in chick embryos. Our analysis indicated in addition to regulatory domains 5' of the transcriptional start site an important regulatory domain resides in intron 1 of the gene itself. This intronic domain functioned both in cell lines and in vivo in the neural tube of the chick embryo including developing motor neurones. Our data suggest the interaction of multiple domains including intronic domains are involved in expression of FUS. A better understanding of the regulation of expression of FUS may give insight into how its stimulus inducible expression may be associated with neurological disorders.
authors.affiliation: Institute of Translational Medicine, Sherrington Buildings, Ashton St, Liverpool University, Liverpool L69 3GE, UK.
authors.forename: Kejhal
authors.initials: K
authors.lastname: Khursheed
authors.affiliation: Institute of Translational Medicine, Sherrington Buildings, Ashton St, Liverpool University, Liverpool L69 3GE, UK.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Wilm
authors.affiliation: Institute of Translational Medicine, Sherrington Buildings, Ashton St, Liverpool University, Liverpool L69 3GE, UK.
authors.forename: Christine
authors.initials: C
authors.lastname: Cashman
authors.affiliation: Institute of Translational Medicine, Sherrington Buildings, Ashton St, Liverpool University, Liverpool L69 3GE, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Quinn
authors.affiliation: Institute of Translational Medicine, Sherrington Buildings, Ashton St, Liverpool University, Liverpool L69 3GE, UK.
authors.forename: Vivien J
authors.initials: VJ
authors.lastname: Bubb
authors.affiliation: Institute of Translational Medicine, Sherrington Buildings, Ashton St, Liverpool University, Liverpool L69 3GE, UK. Electronic address: d.moss@liv.ac.uk.
authors.forename: Diana J
authors.initials: DJ
authors.lastname: Moss
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002642:Chick Embryo; D004195:Disease Models, Animal; D004285:Dogs; D019143:Evolution, Molecular; D018507:Gene Expression Regulation, Developmental; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D051379:Mice; D016472:Motor Neuron Disease / Q000235:genetics*; D009154:Mutation; D009447:Neuroblastoma / Q000473:pathology; D011401:Promoter Regions, Genetic; D034702:RNA-Binding Protein FUS / Q000235:genetics* / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*
chemical_list: D034702:RNA-Binding Protein FUS; D049452:Green Fluorescent Proteins
keywords: ALS; Chick embryo model; Evolutionary conserved domains; FTD; Parkinson׳s disease; Reporter gene assays