CRE-mediated transcription is increased in Huntington's disease transgenic mice.
Disruption of cAMP response element (CRE)-dependent transcription has been hypothesized to contribute to neuronal death and dysfunction in Huntington's disease (HD) and other polyglutamine repeat disorders. Whether dysregulation of CRE-dependent transcription actually occurs in vivo in response to expression of expanded polyglutamine repeats has not been tested. We directly tested whether CRE-dependent transcription is affected in vivo by cross breeding a transgenic mouse model of HD (line R6/2) with a transgenic mouse that expresses a CRE-regulated reporter gene. Instead of compromised CRE-dependent transcription in HD mice, we found a robust upregulation of CRE-dependent transcription in several brain regions (striatum, hippocampus, cortex). CRE-mediated transcription was also evoked by striatal forskolin infusion and by photic stimulation in HD animals. Increased cAMP response element-binding protein (CREB) phosphorylation and elevated levels of the CREB-regulated gene product, CCAAT/enhancer binding protein beta, were also found in HD mice. Significant alterations in CREB binding protein expression and localization were not observed in symptomatic R6/2 mice. Thus, rather than repressing CRE-mediated transcription, mutant huntingtin appears to facilitate transcription via a CRE-dependent mechanism in vivo.
Obrietan
Karl
K
Department of Neuroscience, The Ohio State University, Columbus, Ohio 43210, USA.
Hoyt
Kari R
KR
D000818:Animals; D001921:Brain / Q000378:metabolism; D003433:Crosses, Genetic; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D017930:Genes, Reporter; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics*; D007150:Immunohistochemistry; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D010641:Phenotype; D010766:Phosphorylation; D020218:Response Elements; D014158:Transcription, Genetic; D019680:Trinucleotide Repeat Expansion; D015854:Up-Regulation
D017362:Cyclic AMP Response Element-Binding Protein; C506812:Htt protein, mouse; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins