<i>Atrx</i> deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits

Tamming, Renee J.; Dumeaux, Vanessa; Langlois, Luana; Ellegood, Jacob; Qiu, Lily R.; Jiang, Yan; Lerch, Jason P.; Bérubé, Nathalie G.

doi:10.1101/606442

Cited by 3 publications

(6 citation statements)

References 94 publications

(76 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Results from the open field test can be interpreted in various ways, and therefore, are more powerful when analyzed in combination. Previous work in our lab had identified additional sex-differences in the open field test, with Atrx- cKO FEMALE and Ctrl FEMALE mice spending less time in centre compared to males(21). Decreased time in centre as well as increased vertical episodes in the open field test have been previously interpreted as a demonstration of anxiety-like behaviour (49,50).…”

Section: Discussionmentioning

confidence: 85%

“…Specifically, transcription of autism susceptibility genes, including the monogenic Neuroligin-4 ( Nlgn4) , are altered upon loss of Atrx (19). Additionally, sexually dimorphic transcript changes have been revealed in the adult mouse hippocampus upon the loss of Atrx in excitatory neurons(21). However, autistic behaviours were not evaluated in that report, and should be addressed given the link between ATRX mutations and ASD.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Effects of a postnatalAtrxconditional knockout in neurons on autism-like behaviours in male and female mice

Martin-Kenny

Bérubé

2020

Preprint

Self Cite

View full text Add to dashboard Cite

24Background: Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism 25 susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X 26 intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) 27 patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours 28 are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in 29 excitatory neurons of the forebrain and performed a battery of behavioural assays that assess 30 autistic-like behaviours. 31Methods: Male and female mice with a postnatal conditional knockout of Atrx were tested in a 32 battery of behavioural tests that assess autistic features. We utilized paradigms that measure social 33 behaviour, repetitive and stereotyped behaviours, as well as sensory gating. Statistics were 34 calculated by two-way repeated measures ANOVA with Sidak's multiple comparison test or 35 unpaired Student's T-tests as indicated. 36Results: The behaviour tests revealed no significant differences between Atrx-cKO and control 37 mice. We identified sexually dimorphic changes in odor habituation and discrimination; however, 38 these changes did not correlate with social deficits. We additionally observed sex-specific 39 differences in sociability, vertical episodes, and acoustic startle response when results were 40 analyzed by sex. 41 Conclusion: The postnatal knockout of Atrx in forebrain excitatory neurons does not lead to 42 autism-related behaviours in male or female mice.43 44 Keywords: autism spectrum disorder, ATRX, sex differences, social behaviours, repetitive 45 behaviours, startle response, genetically engineered mice, Cre/loxP system 46 Background 47 Autism spectrum disorder (ASD) is a behaviourally defined condition characterized by 48 deficits in social and communicative abilities, impaired sensory gating, as well as the presence of 49 stereotyped behaviours (1,2). Recent work has highlighted the important contribution of de novo 50 variants and inherited copy number variants in ASD, confirming a strong genetic component of 51 this disease (1-3). Numerous autism susceptibility genes have been identified and shown to share 52 commonalities in synaptic, transcriptional, and epigenetic mechanisms (4-6). Mouse models have 53typically been used to investigate the behavioural implications of genetic mutations associated 54 with ASD (7,8). However, these studies often omit the investigation of the sex-specific effects of 55 these genetic mutations, limiting the potential translational applications. In the general population, 56 ASD occurs at a 4:1 male:female ratio, highlighting the need to study the outcome of genetic 57 mutations in both male and female model systems (1,2). 58In this study, we describe the impact of targeted inactivation of Atrx in glutamatergic 59 neurons on behaviours related to autism in male and female mice. ATRX belongs to the SWI/SNF 60 family of chromatin remodeling factors (9,10). Mutations in ...

show abstract

Section: Discussionmentioning

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Effects of a postnatalAtrxconditional knockout in neurons on autism-like behaviours in male and female mice

Martin-Kenny

Bérubé

2020

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…RT-qPCR analysis of hTERT expression. For each reaction, the equivalent cDNA of 100 ng RNA was used and expression of the gene of interest was achieved by usage of specific primers and the deltadelta C t method as published [47][48][49] . Primer sequences found in Supplementary Table 1.…”

Section: Chromosome-orientation Fish (Co-fish)mentioning

confidence: 99%

Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres

et al. 2021

View full text Add to dashboard Cite

To achieve replicative immortality, cancer cells must activate telomere maintenance mechanisms to prevent telomere shortening. ~85% of cancers circumvent telomeric attrition by re-expressing telomerase, while the remaining ~15% of cancers induce alternative lengthening of telomeres (ALT), which relies on break-induced replication (BIR) and telomere recombination. Although ALT tumours were first reported over 20 years ago, the mechanism of ALT induction remains unclear and no study to date has described a cell-based model that permits the induction of ALT. Here, we demonstrate that infection with Kaposi’s sarcoma herpesvirus (KSHV) induces sustained acquisition of ALT-like features in previously non-ALT cell lines. KSHV-infected cells acquire hallmarks of ALT activity that are also observed in KSHV-associated tumour biopsies. Down-regulating BIR impairs KSHV latency, suggesting that KSHV co-opts ALT for viral functionality. This study uncovers KSHV infection as a means to study telomere maintenance by ALT and reveals features of ALT in KSHV-associated tumours.

show abstract

“…Specifically, transcription of autism susceptibility genes, including the monogenic Neuroligin-4 (Nlgn4), are altered upon loss of Atrx [19]. Additionally, sexually dimorphic transcript changes have been revealed in the adult mouse hippocampus upon the loss of Atrx in excitatory neurons [21]. However, autistic behaviours were not evaluated in that report and should be addressed given the link between ATRX mutations and ASD.…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we characterize the impact of Atrx loss in neurons on autistic-like behaviours in male and female mice. We used the AtrxCamKIICre model [21] where Atrx is ablated in forebrain excitatory neurons postnatally, thus bypassing deleterious effects of ATRX loss-of-function previously observed in neural progenitors during brain development [22,23]. An array of behavioural assays was performed to investigate the presence of autistic-like behaviours, including deficits in sociability, altered sensory gating, and the presence of repetitive or stereotyped behaviours.…”

Section: Introductionmentioning

confidence: 99%

Effects of a postnatal Atrx conditional knockout in neurons on autism-like behaviours in male and female mice

Martin-Kenny

Bérubé

2020

J Neurodevelop Disord

Self Cite

View full text Add to dashboard Cite

Background Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in excitatory neurons of the forebrain and performed a battery of behavioural assays that assess autistic-like behaviours. Methods Male and female mice with a postnatal conditional ablation of ATRX were generated using the Cre/lox system under the control of the αCaMKII gene promoter. These mice were tested in a battery of behavioural tests that assess autistic-like features. We utilized paradigms that measure social behaviour, repetitive, and stereotyped behaviours, as well as sensory gating. Statistics were calculated by two-way repeated measures ANOVA with Sidak’s multiple comparison test or unpaired Student’s t tests as indicated. Results The behaviour tests revealed no significant differences between Atrx-cKO and control mice. We identified sexually dimorphic changes in odor habituation and discrimination; however, these changes did not correlate with social deficits. Conclusion The postnatal knockout of Atrx in forebrain excitatory neurons does not lead to autism-related behaviours in male or female mice.

show abstract

Atrx deletion in neurons leads to sexually-dimorphic dysregulation of miR-137 and spatial learning and memory deficits

Cited by 3 publications

References 94 publications

Effects of a postnatalAtrxconditional knockout in neurons on autism-like behaviours in male and female mice

Effects of a postnatalAtrxconditional knockout in neurons on autism-like behaviours in male and female mice

Oncogenic herpesvirus KSHV triggers hallmarks of alternative lengthening of telomeres

Effects of a postnatal Atrx conditional knockout in neurons on autism-like behaviours in male and female mice

Contact Info

Product

Resources

About