Towards a better understanding of cognitive behaviors regulated by gene expression downstream of activity-dependent transcription factors

Nonaka, Mio; Kim, Ryang; Sharry, Stuart; Matsushima, Ayano; Takemoto-Kimura, Sayaka; Bito, Haruhiko

doi:10.1016/j.nlm.2014.08.010

Cited by 29 publications

(20 citation statements)

References 109 publications

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“…This behavior resembles the behavior in CREBBP mutated individuals [Galera et al, ; Yagihashi et al, ; Waite et al, ], especially with respect to the obsessive‐compulsive behavior and occurrence of anxieties. Likely, the behavior can be explained directly by the disturbed function of the P300 protein [Nonaka et al, ].…”

Section: Discussionmentioning

confidence: 99%

Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations

Fergelot

Belzen

Gils³

et al. 2016

American J of Med Genetics Pt A

111

158

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Rubinstein-Taybi syndrome (RSTS) is a developmental disorder characterized by a typical face and distal limbs abnormalities, intellectual disability, and a vast number of other features. Two genes are known to cause RSTS, CREBBP in 60% and EP300 in 8-10% of clinically diagnosed cases. Both paralogs act in chromatin remodeling and encode for transcriptional co-activators interacting with >400 proteins. Up to now 26 individuals with an EP300 mutation have been published. Here, we describe the phenotype and genotype of 42 unpublished RSTS patients carrying EP300 mutations and intragenic deletions and offer an update on another 10 patients. We compare the data to 308 individuals with CREBBP mutations. We demonstrate that EP300 mutations cause a phenotype that typically resembles the classical RSTS phenotype due to CREBBP mutations to a great extent, although most facial signs are less marked with the exception of a low-hanging columella. The limb anomalies are more similar to those in CREBBP mutated individuals except for angulation of thumbs and halluces which is very uncommon in EP300 mutated individuals. The intellectual disability is variable but typically less marked whereas the microcephaly is more common. All types of mutations occur but truncating mutations and small rearrangements are most common (86%). Missense mutations in the HAT domain are associated with a classical RSTS phenotype but otherwise no genotype-phenotype correlation is detected. Pre-eclampsia occurs in 12/52 mothers of EP300 mutated individuals versus in 2/59 mothers of CREBBP mutated individuals, making pregnancy with an EP300 mutated fetus the strongest known predictor for pre-eclampsia. © 2016 Wiley Periodicals, Inc.

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Section: Discussionmentioning

confidence: 99%

Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations

Fergelot

Belzen

Gils³

et al. 2016

American J of Med Genetics Pt A

111

158

View full text Add to dashboard Cite

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“…In the present study, we identified two hippocampal genes, the brain‐specific activity‐dependent transcription factor Npas4 (neuronal Per‐Arnt‐Sim domain protein 4) and the immediate early gene Arc (activity‐regulated cytoskeleton‐associated protein), as being differentially expressed with ageing, cognitive decline and 11β‐HSD1 deficiency. Given the crucial roles of Npas4 and Arc in the regulation of learning and memory , and their decreased mRNA levels in the hippocampus of aged memory‐impaired (AI) but not unimpaired (AU) wild‐type or 11β‐HSD1‐deficent mice, it is suggested that these proteins may lie in pathways that are important for the preservation of hippocampus‐associated memory in ageing and are maintained by 11β‐HSD1 deficiency/inhibition.…”

Section: Discussionmentioning

confidence: 99%

“…protein), as being differentially expressed with ageing, cognitive decline and 11b-HSD1 deficiency. Given the crucial roles of Npas4 and Arc in the regulation of learning and memory (31,(33)(34)(35)(36)(37), and their decreased mRNA levels in the hippocampus of aged memoryimpaired (AI) but not unimpaired (AU) wild-type or 11b-HSD1-deficent mice, it is suggested that these proteins may lie in pathways that are important for the preservation of hippocampus-associated memory in ageing and are maintained by 11b-HSD1 deficiency/inhibition.…”

Section: Discussionmentioning

confidence: 99%

Decreased Npas4 and Arc mRNA Levels in the Hippocampus of Aged Memory‐Impaired Wild‐Type But Not Memory Preserved 11β‐HSD1 Deficient Mice

Qiu

Dunbar

Noble

et al. 2016

J Neuroendocrinology

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This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Mice deficient in the glucocorticoid-regenerating enzyme 11b-HSD1 resist age-related spatial memory impairment. To investigate the mechanisms and pathways involved, we used microarrays to identify differentially expressed hippocampal genes that associate with cognitive ageing and 11b-HSD1. Aged wild-type mice were separated into memory-impaired and unimpaired relative to young controls according to their performance in the Y-maze. All individual aged 11b-HSD1-deficient mice showed intact spatial memory. The majority of differentially expressed hippocampal genes were increased with ageing (e.g. immune/inflammatory response genes) with no genotype differences. However, the neuronal-specific transcription factor, Npas4, and immediate early gene, Arc, were reduced (relative to young) in the hippocampus of memory-impaired but not unimpaired aged wild-type or aged 11b-HSD1-deficient mice. A quantitative reverse transcriptase-polymerase chain reaction and in situ hybridisation confirmed reduced Npas4 and Arc mRNA expression in memory-impaired aged wild-type mice. These findings suggest that 11b-HSD1 may contribute to the decline in Npas4 and Arc mRNA levels associated with memory impairment during ageing, and that decreased activity of synaptic plasticity pathways involving Npas4 and Arc may, in part, underlie the memory deficits seen in cognitively-impaired aged wild-type mice.

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“…Mechanisms that precisely regulate gene target specificity dictate changes in the complement of neuronal proteins and, ultimately, such critical fates as whether neurons live or die, and whether synaptic connections are appropriately strengthened, weakened, or eliminated during processes such as information storage. Signaling cascades triggered downstream of neuronal activity by neurotransmitters, growth factors, and cytokines can individually and cooperatively induce multiple activity-responsive transcription factors, including CREB, Npas4, MEF2, MeCP2 (Nonaka et al, 2014), and nuclear factor-kappaB (NF-κB) (Shrum and Meffert, 2008). How these discrete transcription factors contribute unique or overlapping functions to disambiguate incoming signals and to orchestrate context appropriate changes in gene expression remains incompletely understood.…”

Section: Introductionmentioning

confidence: 99%

Targeting of NF-κB to Dendritic Spines is Required for Synaptic Signaling and Spine Development

Dresselhaus

Boersma

Meffert

2018

Preprint

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Long-term forms of brain plasticity share a requirement for changes in gene expression induced by neuronal activity. Mechanisms that determine how the distinct and overlapping functions of multiple activity-responsive transcription factors, including nuclear factor kappa B (NF-κB), give rise to stimulus-appropriate neuronal responses remain unclear. We report that the p65/RelA subunit of NF-κB confers subcellular enrichment at neuronal dendritic spines and engineer a p65 mutant that lacks spine-enrichment (ΔSEp65) but retains inherent transcriptional activity equivalent to wild-type p65. Wild-type p65 or ΔSEp65 both rescue NF-κB-dependent gene expression in p65-deficient murine hippocampal neurons responding to diffuse (PMA/ionomycin) stimulation. In contrast, neurons lacking spine-enriched NF-κB are selectively impaired in NF-κB-dependent gene expression induced by elevated excitatory synaptic stimulation (bicuculline or glycine). We used the setting of excitatory synaptic activity during development that produces NF-κB-dependent growth of dendritic spines to test physiological function of spine-enriched NF-κB in an activity-dependent response. Expression of wild-type p65, but not ΔSEp65, is capable of rescuing spine density to normal levels in p65-deficient pyramidal neurons. Collectively, these data reveal that spatial localization in dendritic spines contributes unique capacities to the NF-κB transcription factor in synaptic activity-dependent responses.SIGNIFICANCE STATEMENTExtensive research has established a model in which the regulation of neuronal gene expression enables enduring forms of plasticity and learning. However, mechanisms imparting stimulus-specificity to gene regulation, insuring biologically appropriate responses, remain incompletely understood. NF-κB is a potent transcription factor with evolutionarily-conserved functions in learning and the growth of excitatory synaptic contacts. Neuronal NF-κB is localized in both synapse and somatic compartments, but whether the synaptic pool of NF-κB has discrete functions is unknown. This study reveals that NF-κB enriched in dendritic spines (the postsynaptic sites of excitatory contacts) is selectively required for NF-κB activation by synaptic stimulation and normal dendritic spine development. These results support spatial localization at synapses as a key variable mediating selective stimulus-response coupling.

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Towards a better understanding of cognitive behaviors regulated by gene expression downstream of activity-dependent transcription factors

Cited by 29 publications

References 109 publications

Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations

Phenotype and genotype in 52 patients with Rubinstein–Taybi syndrome caused by EP300 mutations

Decreased Npas4 and Arc mRNA Levels in the Hippocampus of Aged Memory‐Impaired Wild‐Type But Not Memory Preserved 11β‐HSD1 Deficient Mice

Targeting of NF-κB to Dendritic Spines is Required for Synaptic Signaling and Spine Development

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