E-MEXP-835 - Transcription profiling of liver from Csbm/m/Xpa-/- knockout mice to investigate the effect of nucleotide excision repair pathway inactivation
Released on 1 January 2007, last updated on 28 July 2014
Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria caused by a defect in the transcription-coupled repair (TCR) subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csbm/m/Xpa-/- mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csbm/m/Xpa-/- mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis and die before weaning. To investigate whether a disturbance in growth and metabolism could explain the pronounced accelerated organismal deterioration seen in Csbm/m/Xpa-/- mice, we evaluated the liver transcriptome of 15-day old wt, single and double mutant mice (n=4). At this age, the Csbm/m/Xpa-/- pups have not yet become cachectic. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the GH/IGF1 somatotroph axis and oxidative metabolism, increased antioxidant responses, hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csbm/m/Xpa-/- and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural aging and the DNA repair-deficient mice. Importantly, wild type (wt) mice exposed to a low dose of chronic genotoxic stress and adult Csbm/m mutant mice recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.
transcription profiling by array, disease state, genetic modification
George A Garinis <email@example.com>, Gijsbertus van der Horst, Ingrid van der Pluijm
Impaired Genome Maintenance Suppresses the GH/IGF1 Axis in Cockayne Syndrome Mice. van der Pluijm I, Garinis GA, Brandt RM, Gorgels TG, Wijnhoven SW, Diderich KE, de Wit J, Mitchell JR, van Oostrom C, Beems R, Niedernhofer LJ, Velasco S, Friedberg EC, Tanaka K, van Steeg H, Hoeijmakers JH, van der Horst GT. , Europe PMC 17326724
Defective transcription initiation causes postnatal growth failure in a mouse model of NER progeria. Kamileri I, Karakasilioti I, Sideri A, Kosteas T, Tatarakis A, Talianidis I, Garinis GA. , Europe PMC 22323595