title: Loss of FMR2 further emphasizes the link between deregulation of immediate early response genes FOS and JUN and intellectual disability.
abstract: Loss of FMR2 causes Fragile X E (FRAXE) site-associated intellectual disability (ID). FMR2 regulates transcription, promotes alternative splicing with preference for G-quartet structure harbouring exons and is localized to the nuclear speckles. In primary skin fibroblasts from FRAXE patients (n = 8), we found a significant reduction in the number, but a significant increase in the size, of nuclear speckles, when compared with the controls (n = 4). Since nuclear speckles are enriched with factors involved in pre-mRNA processing, we explored the consequence of these defects and the loss of FMR2 on the transcriptome. We performed whole genome expression profiling using total RNA extracted from these cell lines and found 27 genes significantly deregulated by at least 2-fold at P < 0.05 in the patients. Among these genes, FOS was significantly upregulated and was further investigated due to its established role in neuronal cell function. We showed that (i) 30% depletion of Fmr2 in mouse primary cortical neurons led to a 2-fold increase in Fos expression, (ii) overexpression of FMR2 significantly decreased FOS promoter activity in luciferase assays, and (iii) as FOS promoter contains a serum response element, we found that not FOS, but JUN, which encodes for a protein that forms a transcriptional activator complex with FOS, was significantly upregulated in the patients' cell lines upon mitogen stimulation. These results suggest that FMR2 is an upstream regulator of FOS and JUN, and further link deregulation of the immediate early response genes to the pathology of ID- and FRAXE-associated ID in particular.
authors.affiliation: Institut de Pharmacologie Moléculaire et Cellulaire, CNRS UMR 7275, 660 Route des Lucioles, F-06560 Valbonne, France.
authors.forename: Mireille
authors.initials: M
authors.lastname: Melko
authors.forename: Lam S
authors.initials: LS
authors.lastname: Nguyen
authors.forename: Marie
authors.initials: M
authors.lastname: Shaw
authors.forename: Lachlan
authors.initials: L
authors.lastname: Jolly
authors.forename: Barbara
authors.initials: B
authors.lastname: Bardoni
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
mesh_terms: D002460:Cell Line; D005347:Fibroblasts / Q000378:metabolism; D005600:Fragile X Syndrome / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics*; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics*
chemical_list: C099930:AFF2 protein, human; D009687:Nuclear Proteins; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun