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Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction
- Source :
- Human Molecular Genetics
- Publication Year :
- 2010
- Publisher :
- Oxford University Press (OUP), 2010.
-
Abstract
- In polyglutamine diseases including Huntington's disease (HD), mutant proteins containing expanded polyglutamine stretches form nuclear aggregates in neurons. Although analysis of their disease models suggested a significance of transcriptional dysregulation in these diseases, how it mediates the specific neuronal cell dysfunction remains obscure. Here we performed a comprehensive analysis of altered DNA binding of multiple transcription factors using R6/2 HD model mice brains that express an N-terminal fragment of mutant huntingtin (mutant Nhtt). We found a reduction of DNA binding of Brn-2, a POU domain transcription factor involved in differentiation and function of hypothalamic neurosecretory neurons. We provide evidence supporting that Brn-2 loses its function through two pathways, its sequestration by mutant Nhtt and its reduced transcription, leading to reduced expression of hypothalamic neuropeptides. In contrast to Brn-2, its functionally related protein, Brn-1, was not sequestered by mutant Nhtt but was upregulated in R6/2 brain, except in hypothalamus. Our data indicate that functional suppression of Brn-2 together with a region-specific lack of compensation by Brn-1 mediates hypothalamic cell dysfunction by mutant Nhtt.
- Subjects :
- Male
Huntingtin
Mutant
Hypothalamus
Electrophoretic Mobility Shift Assay
Nerve Tissue Proteins
Biology
Mice
Transcription (biology)
Genetics
Huntingtin Protein
Animals
Electrophoretic mobility shift assay
Nuclear protein
Molecular Biology
Transcription factor
In Situ Hybridization
Genetics (clinical)
Homeodomain Proteins
Neurons
POU domain
Reverse Transcriptase Polymerase Chain Reaction
Nuclear Proteins
DNA
Articles
General Medicine
Immunohistochemistry
Molecular biology
Huntington Disease
Microscopy, Fluorescence
Mutation
POU Domain Factors
Subjects
Details
- ISSN :
- 14602083 and 09646906
- Volume :
- 19
- Database :
- OpenAIRE
- Journal :
- Human Molecular Genetics
- Accession number :
- edsair.doi.dedup.....aa37cc55fcc58acbf53de2d33706429b