A point mutation in translation initiation factor eIF2B leads to function--and time-specific changes in brain gene expression
| Autor: | Ron Shamir, Liraz Marom, Igor Ulitsky, Yuval Cabilly, Orna Elroy-Stein |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Time Factors Mutant Gene Expression lcsh:Medicine Developmental and Pediatric Neurology medicine.disease_cause Transcriptome Mice Leukoencephalopathies Gene expression Molecular Cell Biology Neurobiology of Disease and Regeneration lcsh:Science Cells Cultured Myelin Sheath Oligonucleotide Array Sequence Analysis Genetics eIF2 Mutation Multidisciplinary biology Reverse Transcriptase Polymerase Chain Reaction Cell Cycle Brain Gene Expression Regulation Developmental Genomics Eukaryotic Initiation Factor-2B Neurology eIF2B Medicine Research Article Real-Time Polymerase Chain Reaction Molecular Genetics Eukaryotic translation Genetic Mutation medicine Animals Point Mutation RNA Messenger Gene Biology Gene Expression Profiling lcsh:R Computational Biology Demyelinating Disorders Mice Inbred C57BL Disease Models Animal Astrocytes Genetics of Disease biology.protein Protein Translation lcsh:Q Molecular Neuroscience Genome Expression Analysis Biomarkers Neuroscience |
| Zdroj: | PLoS ONE, Vol 6, Iss 10, p e26992 (2011) PLoS ONE |
| ISSN: | 1932-6203 |
| Popis: | Background Mutations in eukaryotic translation initiation factor 2B (eIF2B) cause Childhood Ataxia with CNS Hypomyelination (CACH), also known as Vanishing White Matter disease (VWM), which is associated with a clinical pathology of brain myelin loss upon physiological stress. eIF2B is the guanine nucleotide exchange factor (GEF) of eIF2, which delivers the initiator tRNAMet to the ribosome. We recently reported that a R132H mutation in the catalytic subunit of this GEF, causing a 20% reduction in its activity, leads under normal conditions to delayed brain development in a mouse model for CACH/VWM. To further explore the effect of the mutation on global gene expression in the brain, we conducted a wide-scale transcriptome analysis of the first three critical postnatal weeks. Methodology/Principal Findings Genome-wide mRNA expression of wild-type and mutant mice was profiled at postnatal (P) days 1, 18 and 21 to reflect the early proliferative stage prior to white matter establishment (P1) and the peak of oligodendrocye differentiation and myelin synthesis (P18 and P21). At each developmental stage, between 441 and 818 genes were differentially expressed in the mutant brain with minimal overlap, generating unique time point-specific gene expression signatures. Conclusions The current study demonstrates that a point mutation in eIF2B, a key translation initiation factor, has a massive effect on global gene expression in the brain. The overall changes in expression patterns reflect multiple layers of indirect effects that accumulate as the brain develops and matures. The differentially expressed genes seem to reflect delayed waves of gene expression as well as an adaptation process to cope with hypersensitivity to cellular stress. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|