Polyglutamine-Expanded Ataxin-7 Antagonizes CRX Function and Induces Cone-Rod Dystrophy in a Mouse Model of SCA7

Spada, Albert R. La; Fu, Ying Hui; Sopher, Bryce L.; Libby, Randell T.; Wang, Xuejiao; Li, Lili Y.; Einum, David D.; Huang, Jing; Possin, Daniel E.; Smith, Anthony; Martinez, Refugio A.; Koszdin, Kari L.; Treuting, Piper M.; Ware, Carol B.; Hurley, James B.; Ptáček, Louis J.; Chen, Shiming

doi:10.1016/s0896-6273(01)00422-6

Cited by 244 publications

(226 citation statements)

References 45 publications

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“…However, SCA7 patients suffer from a cone-rod dystrophy. SCA7 knock-in mice and transgenic mice expressing polyQ-ataxin-7 controlled by prion promoter recapitulate degeneration of both cone and rod photoreceptors (La Spada et al, 2001;Yoo et al, 2003). In addition, cone function of R7E transgenic mice is impaired, although to a lesser extent than rod function, as revealed by ERGs (data not shown).…”

Section: Discussionmentioning

confidence: 84%

“…This mouse model reproduced the primary features of SCA7 pathology, including progressive functional alteration, followed by rod degeneration. Other SCA7 models with retinopathy include the transgenic mice expressing polyQ-ataxin-7 using a prion protein promoter (La Spada et al, 2001) and the SCA7 knock-in mice (Yoo et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…Accumulation of polyQ-ataxin-7 in the retina of these mice results in decreased expression of phototransduction genes [e.g., rhodopsin (Rho), rod transducin (Gnat1) and phosphodiesterase β (Pdeb)] (Yoo et al, 2003;Helmlinger et al, 2004b). The expression of rod-specific transcriptional regulators, including cone-rod homeobox (Crx) and neural retina leucine zipper (Nrl), is also reduced (La Spada et al, 2001;Chen et al, 2004b;Abou-Sleymane et al, 2006). As mutations in CRX and NRL lead to human retinal dystrophies (Freund et al, 1997;Sohocki et al, 1998;Bessant et al, 1999;Nishiguchi et al, 2004), SCA7 retinopathy may probably be a consequence of the reduced expression of phototransduction genes.…”

Section: Introductionmentioning

confidence: 99%

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Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

Mérienne¹,

Friedman²,

Akimoto³

et al. 2007

Neurobiology of Disease

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We have approached the role of cellular stress in neurodegenerative diseases caused by polyglutamine expansion (polyQ) in the context of Spinocerebellar ataxia type 7 (SCA7) that includes retinal degeneration. Using the R7E mouse, in which polyQ-ataxin-7 is specifically over-expressed in rod photoreceptors, we previously showed that rod dysfunction correlated to moderate and prolonged activation of the JNK/c-Jun stress pathway. SCA7 retinopathy was also associated with reduced expression of rod-specific genes, including the transcription factor Nrl, which is essential for rod differentiation and function. Here, we report that R7E retinopathy is improved upon breeding with the JunAA knock-in mice, in which JNK-mediated activation of c-Jun is compromised. Expression of Nrl and its downstream targets, which are involved in phototranduction, are partially restored in the JunAA-R7E mice. We further show that c-Jun can directly repress the transcription of Nrl. Our studies suggest that polyQ-induced cellular stress leads to repression of genes necessary for neuronal fate and function.

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

Mérienne¹,

Friedman²,

Akimoto³

et al. 2007

Neurobiology of Disease

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“…Expansion of the poly-glutamine tract of ataxin-7 is associated with a dominant neurological disorder, spinocerebellar ataxia type 7 (SCA7), which features cone-rod dystrophy-like retinal degeneration similar to the pathology linked to CRX mutations. Animal model studies and in vitro functional analysis suggest that Crx is a STAGA-dependent transcription activator (La Spada et al, 2001;Chen et al, 2004;Palhan et al, 2005). A polyglutamine-expanded ataxin-7 disrupts Gcn5 HAT activity, resulting in hypoacetylation of histones on Crx target genes and transcription impairment in a SCA7 transgenic mouse model.…”

Section: Mechanisms Of Actionmentioning

confidence: 99%

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

2008

Self Cite

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Rod and cone photoreceptors in the mammalian retina are special types of neurons that are responsible for phototransduction, the first step of vision. Development and maintenance of photoreceptors require precisely regulated gene expression. This regulation is mediated by a network of photoreceptor transcription factors centered on Crx, an Otx-like homeodomain transcription factor. The cell type (subtype) specificity of this network is governed by factors that are preferentially expressed by rods or cones or both, including the rod-determining factors neural retina leucine zipper protein (Nrl) and the orphan nuclear receptor Nr2e3; and cone-determining factors, mostly nuclear receptor family members. The best-documented of these include thyroid hormone receptor β2 (Trβ2), retinoid related orphan receptor Rorβ, and retinoid X receptor Rxrγ. The appropriate function of this network also depends on general transcription factors and co-factors that are ubiquitously expressed, such as the Sp zinc finger transcription factors and STAGA coactivator complexes. These cell type-specific and general transcription regulators form complex interactomes; mutations that interfere with any of the interactions can cause photoreceptor development defects or degeneration. In this manuscript, we review recent progress on the roles of various photoreceptor transcription factors and interactions in photoreceptor subtype development. We also provide evidence of auto-, para-, and feedback regulation among these factors at the transcriptional level. These protein-protein and protein-promoter interactions provide precision and specificity in controlling photoreceptor subtype-specific gene expression, development and survival. Understanding these interactions may provide insights to more effective therapeutic interventions for photoreceptor diseases.

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“…In contrast, studies on the yeast STAGA homolog SAGA suggested that expression of mutant ataxin-7 disrupted SAGA assembly and decreased HAT activity (McMahon et al 2005;Palhan et al 2005). It was further suggested that a photoreceptorspecific disruption in gene expression was associated with changes in the function of the photoreceptorspecific transcription activator CRX (La Spada et al 2001). It was reported that in mice overexpressing mutant ataxin-7, mutant ataxin-7 interacted with CRX and induced its decrease, as well as a decrease in CRX-mediated gene expression.…”

Section: Sca 7: a Role In Cell-specific Chromatin Structurementioning

confidence: 99%

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

Riley¹,

Orr²

2006

Genes Dev.

132

106

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The polyglutamine disorders are a class of nine neurodegenerative disorders that are inherited gain-of-function diseases caused by expansion of a translated CAG repeat. Even though the disease-causing proteins are widely expressed, specific collections of neurons are more susceptible in each disease, resulting in characteristic patterns of pathology and clinical symptoms. One hypothesis poses that altered protein function is fundamental to pathogenesis, with protein context of the expanded polyglutamine having key roles in diseasespecific processes. This review will focus on the role of the disease-causing polyglutamine proteins in gene transcription and the extent to which the mutant proteins induce disruption of transcription.One of the intriguing developments in human genetics is the identification of a mutational mechanism apparently unique to the human genome, the expansion of unstable nucleotide repeats (Gatchel and Zoghbi 2005). Depending on the genetic context of the unstable repeat, the pathogenic mechanism underlying the disorder can be either a loss-of-function or gain-of-function mutation operating at either the RNA or protein level. A subclass of the unstable repeat disorders is caused by the expansion of an unstable CAG trinucleotide repeat located within the protein encoding region such that the repeat is translated into a stretch of glutamine residues; i.e., the polyglutamine diseases. Although rare as a group, the polyglutamine disorders represent the most common form of inherited neurodegenerative disease. At present, nine disorders make up this class of neurodegenerative disease (Table 1). Initially, it was argued that the genetic similarities among these disorders strongly supported the hypothesis that these disorders shared a common mechanism of pathogenesis entirely dependent on the toxic properties of the polyglutamine tract. This typically centered on the enhanced ability of polyglutamine peptides to form intranuclear aggregates/inclusions (Ross and Poirer 2004). The presence of these aggregates/ inclusions within the nuclei of affected neurons focused attention on the nucleus as the subcellular site important in pathogenesis. After much study, the concept of large aggregates/inclusions of mutant polyglutamine as the pathogenic species has become suspect (Arrasate et al. 2004). However, for many of the polyglutamine disorders, understanding events in the nucleus still remains crucial for comprehending pathogenesis.Expansion of the polyglutamine tract is the trigger for pathogenesis. Yet, it likely does so by acting in concert with the other amino acids of the "host" protein (Orr 2001). This point is nicely illustrated by studies on SCA1 and AR/SBMA. In the case of SCA1, replacing single amino acids in ataxin-1 outside of its polyglutamine tract dramatically reduced the ability of mutant ataxin-1 (ataxin-1[82Q]) to cause disease in vivo (Klement et al. 1998;Emamian et al. 2003). In SBMA, androgen binding to the ligand-binding region in AR is critical for pathogenesis (Katsuno et al. 2002(K...

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Polyglutamine-Expanded Ataxin-7 Antagonizes CRX Function and Induces Cone-Rod Dystrophy in a Mouse Model of SCA7

Cited by 244 publications

References 45 publications

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

Preventing polyglutamine-induced activation of c-Jun delays neuronal dysfunction in a mouse model of SCA7 retinopathy

Regulation of photoreceptor gene expression by Crx-associated transcription factor network

Polyglutamine neurodegenerative diseases and regulation of transcription: assembling the puzzle

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