Dataset Information

Prader-Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition.

ABSTRACT: Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13. In addition to endocrine and developmental issues, PWS presents with behavioural problems including stereotyped behaviour, impulsiveness and cognitive deficits. The PWS genetic interval contains several brain-expressed small nucleolar (sno) RNA species that are subject to genomic imprinting, including snord115 that negatively regulates post-transcriptional modification of the serotonin 2C receptor (5-HT2CR) pre-mRNA potentially leading to a reduction in 5-HT2CR function. Using the imprinting centre deletion mouse model for PWS (PWSICdel) we have previously shown impairments in a number of behaviours, some of which are abnormally sensitive to 5-HT2CR-selective drugs. In the stop-signal reaction time task test of impulsivity, PWSICdel mice showed increased impulsivity relative to wild-type (WT) littermates. Challenge with the selective 5-HT2CR agonist WAY163909 reduced impulsivity in PWSICdel mice but had no effect on WT behaviour. This behavioural dissociation in was also reflected in differential patterns of immunoreactivity of the immediate early gene c-Fos, with a blunted response to the drug in the orbitofrontal cortex of PWSICdel mice, but no difference in c-Fos activation in the nucleus accumbens. These findings suggest specific facets of response inhibition are impaired in PWSICdel mice and that abnormal 5-HT2CR function may mediate this dissociation. These data have implications for our understanding of the aetiology of PWS-related behavioural traits and translational relevance for individuals with PWS who may seek to control appetite with the new obesity treatment 5-HT2CR agonist lorcaserin.

SUBMITTER: Davies JR

PROVIDER: S-EPMC6737253 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Prader-Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition.

Davies Jennifer R JR Wilkinson Lawrence S LS Isles Anthony R AR Humby Trevor T

Human molecular genetics 20190901 18

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13. In addition to endocrine and developmental issues, PWS presents with behavioural problems including stereotyped behaviour, impulsiveness and cognitive deficits. The PWS genetic interval contains several brain-expressed small nucleolar (sno) RNA species that are subject to genomic imprinting, including snord115 that negatively regul ...[more]

PMID: 31087031

Similar Datasets

Project description:Genomic imprinting is a phenomenon that some genes are expressed differentially according to the parent of origin. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders caused by deficiency of imprinted gene expression from paternal and maternal chromosome 15q11-q13, respectively. Imprinted genes at the PWS/AS domain are regulated through a bipartite imprinting center, the PWS-IC and AS-IC. The PWS-IC activates paternal-specific gene expression and is responsible for the paternal imprint, whereas the AS-IC functions in the maternal imprint by allele-specific repression of the PWS-IC to prevent the paternal imprinting program. Although mouse chromosome 7C has a conserved PWS/AS imprinted domain, the mouse equivalent of the human AS-IC element has not yet been identified. Here, we suggest another dimension that the PWS-IC also functions in maternal imprinting by negatively regulating the paternally expressed imprinted genes in mice, in contrast to its known function as a positive regulator for paternal-specific gene expression. Using a mouse model carrying a 4.8-kb deletion at the PWS-IC, we demonstrated that maternal transmission of the PWS-IC deletion resulted in a maternal imprinting defect with activation of the paternally expressed imprinted genes and decreased expression of the maternally expressed imprinted gene on the maternal chromosome, accompanied by alteration of the maternal epigenotype toward a paternal state spread over the PWS/AS domain. The functional significance of this acquired paternal pattern of gene expression was demonstrated by the ability to complement PWS phenotypes by maternal inheritance of the PWS-IC deletion, which is in stark contrast to paternal inheritance of the PWS-IC deletion that resulted in the PWS phenotypes. Importantly, low levels of expression of the paternally expressed imprinted genes are sufficient to rescue postnatal lethality and growth retardation in two PWS mouse models. These findings open the opportunity for a novel approach to the treatment of PWS.

Project description:Prader-Willi syndrome (PWS) is caused by loss of paternally expressed genes in the 15q11-q13 region. To further characterize alterations in gene expression in this classical obesity syndrome we used whole genome microarrays to study a PWS mouse model resulting from a paternally derived imprinting center (IC) deletion (PWS IC deletion). These mice die generally within 2-3 days of life (reflective of failure to thrive in infants with PWS) and therefore, the analysis was performed on RNA extracted from the whole brain of PWS IC deletion mice and normal littermates at less than 24 hr after birth. Of more than 45,000 probes examined, 26,471 (59%) were detected for further analysis, and 69 had a significant change in expression of at least 1.5-fold and a false discovery rate (FDR) of 5%. Eight of the genes with differential expression were imprinted and from the PWS critical region (PWSCR). The three genes with the highest expression in the PWS IC mice were pro-opiomelanocortin (Pomc) and two transcripts of unknown function. Pomc knockout mice have been shown to develop obesity. Therefore, elevated Pomc RNA in PWS IC deletion neonatal mice may be an important genetic factor in the survival of these mice as it may affect eating behavior. Interestingly, Mc5r, a melanocortin receptor known to directly respond to Pomc expression changes, was upregulated as well. Mc5r is known to be involved with thermoregulation which is reportedly abnormal in PWS infants. These observations support a role for Pomc and the network of genes involved in regulating energy homeostasis in the early clinical findings of failure to thrive observed in PWS. Other notable patterns include three previously unstudied transcripts that are expressed only from the paternal allele under regulatory control of the IC and include AK013560, BB3144814, and BB182944 (whose genes are located in the mouse PWSCR on chromosome 7B). As expected, all the known paternally expressed genes from the PWSCR had detection signals below the threshold in the PWS IC deletion mice but were clearly detectable in control littermates. Several of the genes in this study were further examined by quantitative reverse transcription-PCR (RT-PCR) to confirm their expression status. Further analysis of gene expression in these mice may lead to novel pathways affected in PWS. These results, along with other recent reports, suggest that the cumulative effect of modest changes in expression of many genes, especially genes involved in energy metabolism, contribute to the failure to thrive of infants with PWS.

Project description:Study objectivesSleep-wake disturbances are often reported in Prader-Willi syndrome (PWS), a rare neurodevelopmental syndrome that is associated with paternally-expressed genomic imprinting defects within the human chromosome region 15q11-13. One of the candidate genes, prevalently expressed in the brain, is the small nucleolar ribonucleic acid-116 (SNORD116). Here we conducted a translational study into the sleep abnormalities of PWS, testing the hypothesis that SNORD116 is responsible for sleep defects that characterize the syndrome.MethodsWe studied sleep in mutant mice that carry a deletion of Snord116 at the orthologous locus (mouse chromosome 7) of the human PWS critical region (PWScr). In particular, we assessed EEG and temperature profiles, across 24-h, in PWScr (m+/p-) heterozygous mutants compared to wild-type littermates. High-resolution magnetic resonance imaging (MRI) was performed to explore morphoanatomical differences according to the genotype. Moreover, we complemented the mouse work by presenting two patients with a diagnosis of PWS and characterized by atypical small deletions of SNORD116. We compared the individual EEG parameters of patients with healthy subjects and with a cohort of obese subjects.ResultsBy studying the mouse mutant line PWScr(m+/p-), we observed specific rapid eye movement (REM) sleep alterations including abnormal electroencephalograph (EEG) theta waves. Remarkably, we observed identical sleep/EEG defects in the two PWS cases. We report brain morphological abnormalities that are associated with the EEG alterations. In particular, mouse mutants have a bilateral reduction of the gray matter volume in the ventral hippocampus and in the septum areas, which are pivotal structures for maintaining theta rhythms throughout the brain. In PWScr(m+/p-) mice we also observed increased body temperature that is coherent with REM sleep alterations in mice and human patients.ConclusionsOur study indicates that paternally expressed Snord116 is involved in the 24-h regulation of sleep physiological measures, suggesting that it is a candidate gene for the sleep disturbances that most individuals with PWS experience.

Dataset Information

Prader-Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition.

Publications

Prader-Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets