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Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction.

Yamanaka T, Tosaki A, Miyazaki H, Kurosawa M, Furukawa Y, Yamada M, Nukina N - Hum. Mol. Genet. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.

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.

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Hypothetical model. (A) In control mouse brain, Brn-2 is involved in the expression of neuropeptides in hypothalamus, whereas both Brn-2 and Brn-1 are involved in the expression of their target genes including p39 in cortex. Arnt2 regulates Brn-2 expression only in hypothalamus by forming a protein complex with its hypothalamus-specific co-factor, Sim1. (B) In R6/2 HD model mouse brain, mutant Nhtt sequesters Brn-2, leading to a reduction of functional Brn-2. Mutant Nhtt also sequesters Arnt2 to reduce the functional Arnt2-Sim1 complex, which further contributes to the reduction of functional Brn-2 by its reduced transcription. The suppression of Brn-2 as well as a lack of upregulation of Brn-1 leads to reduced expressions of neuropeptides in hypothalamus. In contrast, expressions of cortical Brn-1/2 targets including p39 are not affected possibly because of compensation of Brn-2 suppression by upregulated Brn-1.
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DDQ087F9: Hypothetical model. (A) In control mouse brain, Brn-2 is involved in the expression of neuropeptides in hypothalamus, whereas both Brn-2 and Brn-1 are involved in the expression of their target genes including p39 in cortex. Arnt2 regulates Brn-2 expression only in hypothalamus by forming a protein complex with its hypothalamus-specific co-factor, Sim1. (B) In R6/2 HD model mouse brain, mutant Nhtt sequesters Brn-2, leading to a reduction of functional Brn-2. Mutant Nhtt also sequesters Arnt2 to reduce the functional Arnt2-Sim1 complex, which further contributes to the reduction of functional Brn-2 by its reduced transcription. The suppression of Brn-2 as well as a lack of upregulation of Brn-1 leads to reduced expressions of neuropeptides in hypothalamus. In contrast, expressions of cortical Brn-1/2 targets including p39 are not affected possibly because of compensation of Brn-2 suppression by upregulated Brn-1.

Mentions: In this study, we performed screening of affected transcription factors in R6/2 HD model mouse brains using a new strategy and identified a novel factor, Brn-2, whose DNA binding was reduced in these brains. Importantly, Brn-2 was sequestered by mutant Nhtt by co-aggregation. We also found evidence that mutant Nhtt reduced Brn-2 transcription in hypothalamic neurons possibly through sequestering Brn-2-upstream regulator, Arnt2. Finally, we showed the reduction of functional Brn-2 in addition to reduced expressions of VP, OT and CRH in hypothalamus of R6/2 without obvious cell loss. These data indicate that Brn-2 loses its function through two pathways, its sequestration by mutant Nhtt and its reduced transcription, resulting in the reduced transcriptions of VP, OT and CRH (Fig. 9). Thus, our screening-based analysis could identify novel mutant Nhtt target, Brn-2, which mediates hypothalamic cell dysfunction in HD model mouse brain.


Mutant huntingtin fragment selectively suppresses Brn-2 POU domain transcription factor to mediate hypothalamic cell dysfunction.

Yamanaka T, Tosaki A, Miyazaki H, Kurosawa M, Furukawa Y, Yamada M, Nukina N - Hum. Mol. Genet. (2010)

Hypothetical model. (A) In control mouse brain, Brn-2 is involved in the expression of neuropeptides in hypothalamus, whereas both Brn-2 and Brn-1 are involved in the expression of their target genes including p39 in cortex. Arnt2 regulates Brn-2 expression only in hypothalamus by forming a protein complex with its hypothalamus-specific co-factor, Sim1. (B) In R6/2 HD model mouse brain, mutant Nhtt sequesters Brn-2, leading to a reduction of functional Brn-2. Mutant Nhtt also sequesters Arnt2 to reduce the functional Arnt2-Sim1 complex, which further contributes to the reduction of functional Brn-2 by its reduced transcription. The suppression of Brn-2 as well as a lack of upregulation of Brn-1 leads to reduced expressions of neuropeptides in hypothalamus. In contrast, expressions of cortical Brn-1/2 targets including p39 are not affected possibly because of compensation of Brn-2 suppression by upregulated Brn-1.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC2865370&req=5

DDQ087F9: Hypothetical model. (A) In control mouse brain, Brn-2 is involved in the expression of neuropeptides in hypothalamus, whereas both Brn-2 and Brn-1 are involved in the expression of their target genes including p39 in cortex. Arnt2 regulates Brn-2 expression only in hypothalamus by forming a protein complex with its hypothalamus-specific co-factor, Sim1. (B) In R6/2 HD model mouse brain, mutant Nhtt sequesters Brn-2, leading to a reduction of functional Brn-2. Mutant Nhtt also sequesters Arnt2 to reduce the functional Arnt2-Sim1 complex, which further contributes to the reduction of functional Brn-2 by its reduced transcription. The suppression of Brn-2 as well as a lack of upregulation of Brn-1 leads to reduced expressions of neuropeptides in hypothalamus. In contrast, expressions of cortical Brn-1/2 targets including p39 are not affected possibly because of compensation of Brn-2 suppression by upregulated Brn-1.
Mentions: In this study, we performed screening of affected transcription factors in R6/2 HD model mouse brains using a new strategy and identified a novel factor, Brn-2, whose DNA binding was reduced in these brains. Importantly, Brn-2 was sequestered by mutant Nhtt by co-aggregation. We also found evidence that mutant Nhtt reduced Brn-2 transcription in hypothalamic neurons possibly through sequestering Brn-2-upstream regulator, Arnt2. Finally, we showed the reduction of functional Brn-2 in addition to reduced expressions of VP, OT and CRH in hypothalamus of R6/2 without obvious cell loss. These data indicate that Brn-2 loses its function through two pathways, its sequestration by mutant Nhtt and its reduced transcription, resulting in the reduced transcriptions of VP, OT and CRH (Fig. 9). Thus, our screening-based analysis could identify novel mutant Nhtt target, Brn-2, which mediates hypothalamic cell dysfunction in HD model mouse brain.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Laboratory for Structural Neuropathology, RIKEN Brain Science Institute, Saitama 351-0198, Japan.

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.

Show MeSH
Related in: MedlinePlus