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Loss of Snord116 impacts lateral hypothalamus, sleep, and food-related behaviors

ABSTRACT: Imprinted genes are highly expressed in the hypothalamus, however whether specific imprinted genes affect hypothalamic neuromodulators and their functions is unknown. It has been suggested that Prader-Willi syndrome (PWS), a neurodevelopmental disorder caused by lack of paternal expression at the chromosome 15q11-q13, characterised with a hypothalamic insufficiency. Here we investigate the role of paternally expressed Snord116 gene within the context of sleep and metabolic abnormalities of PWS, and we report a novel role of this imprinted gene in the function and organisation of the two main neuromodulatory systems of the lateral hypothalamus (LH), namely the orexin (OX) and the melanin concentrating hormone (MCH). We observe that the dynamic between neuronal discharge in the LH and sleep-wake states of mice carrying the paternal deletion of the Snord116 (PWScrm+/p-) is compromised. This abnormal state-dependent neuronal activity is paralleled by a significant reduction of OX neurons in LH of mutants. Therefore, we propose that unbalance between OX- and MCH- expressing neurons in the LH of mutants reflects in a series of deficits manifested in the PWS, such as dysregulation of rapid eye movement (REM) sleep, food intake and temperature control.

ORGANISM(S): Mus musculus

PROVIDER: GSE139524 | GEO | 2020/05/25

REPOSITORIES: GEO

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Project description:We performed gene expression microarray analysis of the hypothalamic response to starvation in neonatal wild-type mice, and in Snord116del mice that are a mouse model for PWS. This study is motivated by the neonatal feeding problems observed in several genetic diseases including Prader-Willi syndrome (PWS). Later in life, individuals with PWS develop hyperphagia and obesity due to lack of appetite control. We hypothesize that failure to thrive in infancy and later-onset hyperphagia may be related and could be due to a defect in the hypothalamus. In this study, we performed gene expression microarray analysis of the hypothalamic response to starvation in neonatal wild-type mice, and in Snord116del mice that are a mouse model for PWS. The neonatal starvation response was dramatically different from that reported in adult rodents. Genes that are affected by adult starvation are not changed in the hypothalamus of 5 day-old pups that were starved for 6 hrs. Unlike in adult rodents, expression levels of Nanos2 and Pdk4 were increased, and those of Pgpep1, Ndph, Brms1l, Mett10d, and Snx1 were decreased after fasting. In addition, we compared hypothalamic gene expression profiles at days 5 and 13 to document developmental changes. Notably, the gene expression profiles of Snord116del deletion mice and wild-type littermates were very similar at both postnatal days 5 and 13, and after starvation. We compared hypothalamic RNA between Snord116del mice with wild type (C57BL/6J) littermates at P5 and P13, with or without fasting treatment. We are particularly interested in the following comparisons: Comparison 1: wild type vs. PWS deletion in P5 non-starved mice; Comparison 2: wild type vs. PWS deletion in P5 fasting mice; Comparison 3: non-starved vs. fasting in P5 wild type mice; Comparison 4: non-starved vs. fasting in P5 PWS deletion mice; Comparison 5: wild type vs. PWD deletion in P13 non-starved mice; Comparison 6: P5 wild type vs. P13 wild type mice;

Project description:Introduction: A microdeletion including the SNORD116 gene (SNORD116 MD) has been shown to drive the Prader-Willi syndrome (PWS) phenotype. PWS is a neurodevelopmental disorder resulting from hypothalamic dysfunction implicating oxytocin (OXT) circuits. It is clinically characterized by early severe obesity, endocrine impairment, intellectual disability and psychiatric symptoms such as a lack of emotional regulation, impulsivity, and intense temper tantrums with outbursts. In addition, this syndrome is associated with a nutritional trajectory characterized by addiction-like behavior around food in adulthood. PWS is related to the genetic loss of expression of a minimal region of chromosome 15 encompassing the SNORD116 gene, encoding for a long noncoding RNA that plays a potential role in epigenetic regulation. Nevertheless, the role of the SNORD116 MD in DNA methylation, as well as the impact of OXT on it, have never been investigated in human neurons. Methods: We studied the methylation marks in dopaminergic neurons issued from induced pluripotent stem neuronsscells (iPSC) carrying a SNORD116 MD in comparison with those from an age-matched adult healthy control. We also performed identical neurons differentiation in the presence of OXT. We performed a genome-wide DNA methylation analysis from iPSC-derived dopaminergic neurons by reduced-representation bisulfite sequencing. In addition, we performed RNA sequencing analysis in the iPSC-derived dopaminergic neurons differentiated with or without OXT. Results: The analysis revealed that among the differentially methylated genes, we determined a list of gene also differentially expressed. Enrichment analysis of this list encompassed dopaminergic system with COMT and SLC6A3.RT-qPCR attested significant over expression of SLC6A3 in SNORD116 MD neuronss. Moreover, the expression of this gene was significantly decreased in case of OXT adjunction during the differentiation. . Conclusion: SNORD116 MD dopaminergic neurons display differential methylation and expression in genes related to dopaminergic clearance .

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Loss of Snord116 impacts lateral hypothalamus, sleep, and food-related behaviors

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