Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.

Ingrid Van Der Pluijm, George A. Garinis, Renata M.C. Brandt, Theo G.M.F. Gorgels, Susan W. Wijnhoven, Karin E.M. Diderich, Jan De Wit, James R. Mitchell, Conny Van Oostrom, Rudolf Beems, Laura J. Niedernhofer, Susana Velasco, Errol C. Friedberg, Kiyoji Tanaka, Harry Van Steeg, Jan H.J. Hoeijmakers, Gijsbertus T.J. Van Der Horst

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Abstract

Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.

Original languageEnglish (US)
JournalPLoS Biology
Volume5
Issue number1
DOIs
StatePublished - Dec 12 2006

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Cockayne Syndrome
somatomedins
Somatomedins
somatotropin
Growth Hormone
DNA repair
Repair
Genes
Maintenance
Genome
genome
DNA Repair
Somatotrophs
mice
Liver
liver
Nucleotides
Progeria
DNA Repair-Deficiency Disorders
cachexia

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

Van Der Pluijm, I., Garinis, G. A., Brandt, R. M. C., Gorgels, T. G. M. F., Wijnhoven, S. W., Diderich, K. E. M., ... Van Der Horst, G. T. J. (2006). Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome. PLoS Biology, 5(1). https://doi.org/10.1371/journal.pbio.0050002

Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome. / Van Der Pluijm, Ingrid; Garinis, George A.; Brandt, Renata M.C.; Gorgels, Theo G.M.F.; Wijnhoven, Susan W.; Diderich, Karin E.M.; De Wit, Jan; Mitchell, James R.; Van Oostrom, Conny; Beems, Rudolf; Niedernhofer, Laura J.; Velasco, Susana; Friedberg, Errol C.; Tanaka, Kiyoji; Van Steeg, Harry; Hoeijmakers, Jan H.J.; Van Der Horst, Gijsbertus T.J.

In: PLoS Biology, Vol. 5, No. 1, 12.12.2006.

Research output: Contribution to journalArticle

Van Der Pluijm, I, Garinis, GA, Brandt, RMC, Gorgels, TGMF, Wijnhoven, SW, Diderich, KEM, De Wit, J, Mitchell, JR, Van Oostrom, C, Beems, R, Niedernhofer, LJ, Velasco, S, Friedberg, EC, Tanaka, K, Van Steeg, H, Hoeijmakers, JHJ & Van Der Horst, GTJ 2006, 'Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome.', PLoS Biology, vol. 5, no. 1. https://doi.org/10.1371/journal.pbio.0050002
Van Der Pluijm, Ingrid ; Garinis, George A. ; Brandt, Renata M.C. ; Gorgels, Theo G.M.F. ; Wijnhoven, Susan W. ; Diderich, Karin E.M. ; De Wit, Jan ; Mitchell, James R. ; Van Oostrom, Conny ; Beems, Rudolf ; Niedernhofer, Laura J. ; Velasco, Susana ; Friedberg, Errol C. ; Tanaka, Kiyoji ; Van Steeg, Harry ; Hoeijmakers, Jan H.J. ; Van Der Horst, Gijsbertus T.J. / Impaired genome maintenance suppresses the growth hormone--insulin-like growth factor 1 axis in mice with Cockayne syndrome. In: PLoS Biology. 2006 ; Vol. 5, No. 1.
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abstract = "Cockayne syndrome (CS) is a photosensitive, DNA repair disorder associated with progeria that is caused by a defect in the transcription-coupled repair subpathway of nucleotide excision repair (NER). Here, complete inactivation of NER in Csb(m/m)/Xpa(-/-) mutants causes a phenotype that reliably mimics the human progeroid CS syndrome. Newborn Csb(m/m)/Xpa(-/-) mice display attenuated growth, progressive neurological dysfunction, retinal degeneration, cachexia, kyphosis, and die before weaning. Mouse liver transcriptome analysis and several physiological endpoints revealed systemic suppression of the growth hormone/insulin-like growth factor 1 (GH/IGF1) somatotroph axis and oxidative metabolism, increased antioxidant responses, and hypoglycemia together with hepatic glycogen and fat accumulation. Broad genome-wide parallels between Csb(m/m)/Xpa(-/-) and naturally aged mouse liver transcriptomes suggested that these changes are intrinsic to natural ageing and the DNA repair-deficient mice. Importantly, wild-type mice exposed to a low dose of chronic genotoxic stress recapitulated this response, thereby pointing to a novel link between genome instability and the age-related decline of the somatotroph axis.",
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