Biology subjects

Isles, A.

Publications and source records attributed to Isles, A..

8 recordsLinked to original sources

bioRxiv2026

Prader-Willi syndrome genes are expressed in placenta and play a role in function

The neurodevelopmental disorder Prader-Willi syndrome (PWS) is caused by loss of paternally-derived gene expression from the imprinted interval on chromosome 15q11-q13. Recently, it has been suggested that the abnormal feeding-related behaviours characteristic of PWS may, in part, be developmentally programmed in utero via abnormal placental function. Here we report that several PWS-genes are expressed in mouse placenta with three PWS-transcripts Magel2, Necdin and the lncRNA Sngh14, co-localising to the Kdr-positive fetal endothelial cells of the labyrinth zone central to nutrient transport. In a novel PWS deletion mouse model (Large+/-) we find markedly reduced expression of PWS genes in the placenta and an associated [~]25% reduction in Kdr-positive fetal endothelial cells. Although this did not directly translate into a significant reduction in fetal growth late in gestation, these data suggest that placental function and nutrient transfer from mother to fetus could be compromised in PWS contributing to later post-natal phenotypes. Summary statementReduced expression of PWS-associated genes in the mouse placenta results in a 25% loss of the fetal endothelial cells that play a central role in nutrient and gas exchange.

physiology↗

bioRxiv2021

Behavioural consequences of Setd1a haploinsufficiency in mice: evidence for heightened emotional reactivity and impaired sensorimotor gating

A number of studies implicate the loss of function (LoF) mutations affecting the histone methyl transferase SETD1A in the aetiology of a range of neurodevelopmental disorders including schizophrenia. Here, we examined the behavioural consequences of haploinsufficiency of Setd1a in a mouse model. We find evidence for changes in a number of phenotypes of relevance to schizophrenia, including increased anxiety-related behaviour, enhanced acoustic startle response, and decreased pre-pulse inhibition of acoustic startle. The sensorimotor gating deficits in Setd1a+/- mice could not be rescued by haloperidol or risperidone, suggesting that these antipsychotics are ineffective for ameliorating schizophrenia-relevant phenotypes in Setd1a+/- mice and point to deficits in neural systems other than the monoamine system. These phenotypes are emerging as key features of a number of other mouse models of rare neurodevelopmental disorders caused by LoF mutations in genes encoding epigenome modifiers suggesting they may act in a network to modulate brain development. Taken together these data strengthen the support for the use of Setd1a haploinsufficient mice as a model for the biological basis of schizophrenia, and point towards possible underpinning neural mechanisms.

neuroscience↗

bioRxiv2021

Comparison of mouse models reveals the molecular bases for psychotic illness in Prader-Willi syndrome

Prader-Willi Syndrome (PWS) is a neurodevelopmental disorder caused by mutations affecting paternal chromosome 15q11-q13, and characterized by hypotonia, hyperphagia, impaired cognition and behavioural problems. Psychotic illness is a challenging problem for individuals with PWS and has different rates of prevalence in distinct PWS genotypes. Previously, we demonstrated behavioural and cognitive endophenotypes of relevance to psychiatric illness in a mouse model for one of the associated PWS genotypes, namely PWS-IC, in which deletion of the imprinting centre leads to loss of paternal imprinted gene expression and over-expression of Ube3a. Here we examine the broader gene expression changes that are specific to the psychiatric endophenotypes seen in this model. To do this we compared the brain transcriptomic profile of the PWS-IC mouse to the PWS-cr model that carries a deletion of the PWS minimal critical interval spanning the snoRNA Snord116 and Ipw. Firstly, we examined the same behavioural and cognitive endophenotypes of relevance to psychiatric illness in the PWS-cr mice. Unlike the PWS-IC mice, PWS-cr exhibit no differences in locomotor activity, sensory-motor gating, and attention. RNA-seq analysis of neonatal whole brain tissue revealed a greater number of transcriptional changes between PWS-IC and wild-type littermates, than between PWS-cr and wild-type littermates. Moreover, the differentially expressed genes in the PWS-IC brain were enriched for GWAS variants of episodes of psychotic illness but, interestingly, not schizophrenia. These data illustrate the molecular pathways that may underpin psychotic illness in PWS and have implication for potential therapeutic interventions.

neuroscience↗

bioRxiv2020

Mice carrying paternal knockout of imprinted Grb10 do not show compulsive behaviours

Mice lacking paternal expression of imprinted Grb10 show a number of social behaviour deficits, including an enhanced allogrooming phenotype. However, this could also index compulsive behaviour, and the increased whisker barbering seen in Grb10+/p mice has been suggested to be indicative of a trichotillomania-type behaviour. Here we test whether compulsive behaviour is a more general phenotype in Grb10+/p mice by examining marble burying. We also examined the mice for potentially confounding anxiety phenotypes using the elevated plus maze (EPM). Grb10+/p mice showed no difference from wild-type littermate controls on any measure in the marble burying test at any age. However, Grb10+/p mice were more willing to enter, spend time on, and head-dip on the open arm of the EPM than wild-type mice. These data suggest that Grb10+/p mice are not generally more compulsive, and that the enhanced allogrooming is probably indicative of altered social behaviour. Furthermore, the altered behaviours seen on the EPM adds to other published findings suggesting that Grb10 has a role in mediating risk-taking.

animal behavior and cognition↗

bioRxiv2020

Mice lacking paternal expression of imprinted Grb10 are risk-takers

The imprinted genes Grb10 and Nesp influence impulsive behavior on a delay discounting task in an opposite manner. A recently developed theory suggests that this pattern of behavior may be representative of predicted effects of imprinted genes on tolerance to risk. Here we examine whether mice lacking paternal expression of Grb10 show abnormal behavior across a number of measures indicative of risk-taking. Although Grb10+/p mice show no difference from wild type littermates in their willingness to explore a novel environment, their behavior on an explicit test of risk-taking, namely the Predator Odour Risk-Taking task, is indicative of an increased willingness to take risks. Follow-up tests suggest that this risk-taking is not simply due to a general decrease in fear, or a general increase in motivation for a food reward, but reflects a change in the trade-off between cost and reward. These data, coupled with previous work on the impulsive behaviour of Grb10+/p mice in the delayed reinforcement task, and taken together with our work on mice lacking maternal Nesp, suggest that maternally and paternally expressed imprinted genes oppositely influence risk-taking behaviour as predicted.

genetics↗

bioRxiv2018

Detailed analysis of paternal knockout Grb10 mice suggests effects on social stability, rather than social dominance

Imprinted genes are highly expressed in monoaminergic regions of the midbrain and their functions in this area are thought to have an impact on mammalian social behaviors. One such imprinted gene is Grb10, of which the paternal allele is currently recognized as mediating social dominance behavior. However, there has been no detailed study of social dominance in Grb10+/p mice. Moreover, the original study examined tube-test behavior in isolated mice 10 months of age. Isolation testing favors more territorial and aggressive behaviors, and does not address social dominance strategies employed in group housing contexts. Furthermore, isolation stress impacts midbrain function and dominance related behavior, often through alterations in monoaminergic signaling. Thus, we undertook a systematic study of Grb10+/p social rank and dominance behavior within the cage group, using a number of convergent behavioral tests. We examined both male and female mice to account for sex differences, and tested cohorts aged 2, 6, and 10 months to examine any developments related to age. We found group-housed Grb10+/p mice do not show evidence of enhanced social dominance, but cages containing Grb10+/p and wildtype mice lacked the normal correlation between three different measures of social rank. Moreover, a separate study indicated isolation stress induced inconsistent changes in tube test behavior. Taken together, these data suggest future research on Grb10+/p mice should focus on social stability, rather than dominance per se.

animal behavior and cognition↗

bioRxiv2018

Impulsive choice in mice lacking paternal expression of Grb10 provides evidence for intra-genomic conflict in behavior

Imprinted genes are expressed from one parental allele only as a consequence of epigenetic events that take place in the mammalian germ line and are thought to have evolved through intra-genomic conflict between parental alleles. We demonstrate, for the first time, oppositional effects of imprinted genes on brain and behavior. Specifically, here we show that mice lacking paternal Grb10 make fewer impulsive choices, with no dissociable effects on a separate measure of impulsive action. Taken together with previous work showing that mice lacking maternal Nesp55 make more impulsive choices this suggests that impulsive choice behavior is a substrate for the action of genomic imprinting. Moreover, the contrasting effect of these two genes suggests impulsive choices are subject to intra-genomic conflict and that maternal and paternal interests pull this behavior in opposite directions. Finally, these data may also indicate that an imbalance in expression of imprinted genes contributes to pathological conditions such as gambling and drug addiction, where impulsive behavior becomes maladaptive.

genetics↗

bioRxiv2018

Ehmt1 forebrain haploinsufficiency leads to impaired memory, sensory gating and information processing

Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders (NDDs). Haploinsufficiency of EHMT1, encoding a histone methyl-transferase, is associated with several NDDs, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of Ehmt1 haploinsufficiency (Ehmt1D6Cre/+), we examined a number of brain and behavioural endophenotypes of relevance to NDDs. Specifically, we show that Ehmt1D6Cre/+ mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity (MMN). The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions in phase synchronisation. The pattern of electrophysiological deficits in Ehmt1D6Cre/+ matches those seen in control mice following administration of the selective NMDA-R antagonist, ketamine. This, coupled with reduction of Grin1 mRNA expression in Ehmt1D6Cre/+ hippocampus, suggests that Ehmt1 haploinsufficiency may lead to disruption in NMDA-R. Taken together, these data indicate that reduced Ehmt1 dosage during forebrain development leads to abnormal circuitry formation, which in turn results in profound information processing deficits. Such information processing deficits are likely paramount to our understanding of the cognitive and neurological dysfunctions shared across the NDDs associated with EHMT1 haploinsufficiency.

neuroscience↗