Embryonic stem cells expressing expanded CAG repeats undergo aberrant neuronal differentiation and have persistent Oct-4 and REST/NRSF expression.
Nine neurodegenerative disorders are caused by CAG/polyglutamine (polyQ) repeat expansions. The molecular mechanisms responsible for disease-specific neurodegeneration remain elusive. We developed an embryonic stem (ES) cell-based model to probe the role of polyQ tract expansion in neuronal degeneration. ES cells containing expanded CAG repeats in the hypoxanthine phosphoribosyltransferase (Hprt) gene develop features typical of CAG-mediated neuropathology, exhibit length-dependent decrease in survival, undergo aberrant neuronal differentiation as well as persistent Oct-4 and Repressor element-1 transcription factor/neuron restrictive silencer factor (REST/NRSF) expression. This novel model will allow analysis of the molecular pathogenesis of neuronal degeneration and can be used to rapidly screen therapeutic interventions for these fatal diseases.
Lorincz
Matthew T
MT
Department of Neurology, University of Michigan School of Medicine, Ann Arbor, MI 48109, USA. lorincz@umich.edu
Detloff
Peter J
PJ
Albin
Roger L
RL
O'Shea
K Sue
KS
D002454:Cell Differentiation / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020271:Heredodegenerative Disorders, Nervous System / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics; D008954:Models, Biological; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D050814:Octamer Transcription Factor-3; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019680:Trinucleotide Repeat Expansion / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
D004268:DNA-Binding Proteins; D007041:Hypoxanthine Phosphoribosyltransferase; D050814:Octamer Transcription Factor-3; D010455:Peptides; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor; C494173:POU5F1 protein, human; C097188:polyglutamine