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

Pace, Marta; Falappa, Matteo; Freschi, Andrea; Balzani, Edoardo; Berteotti, Chiara; Martire, Viviana Lo; Kaveh, Fatemeh; Hovig, Eivind; Zoccoli, Giovanna; Amici, Roberto; Cerri, Matteo; Urbanucci, Alfonso; Tucci, Valter

doi:10.1172/jci.insight.137495

Cited by 20 publications

(29 citation statements)

References 73 publications

(94 reference statements)

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“…In addition, magnetic resonance imaging revealed a decrease of grey-matter volume in the ventral hippocampus and septum areas of PWScr m+/p− mice [ 89 ]. Orexin and melanin concentrating hormone systems in the lateral hippocampus were impaired in mutant mice, as the deletion of Snord116 gene cluster causes a 60% reduction in orexin expressing neurons [ 88 ]. Consequently, expression of pOx (prepro-orexin) and Peg3 (paternally imprinted gene 3) were significantly upregulated in PWScr m+/p− [ 88 ].…”

Section: Snord116 Gene Clustermentioning

confidence: 99%

“…Orexin and melanin concentrating hormone systems in the lateral hippocampus were impaired in mutant mice, as the deletion of Snord116 gene cluster causes a 60% reduction in orexin expressing neurons [ 88 ]. Consequently, expression of pOx (prepro-orexin) and Peg3 (paternally imprinted gene 3) were significantly upregulated in PWScr m+/p− [ 88 ]. The analysis of RNA-seq data led to the identification of >4000 differentially regulated genes in the hypothalamus of PWScr m+/p− mice compared to wild-type controls [ 88 ].…”

Section: Snord116 Gene Clustermentioning

confidence: 99%

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A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

Kummerfeld

Raabe

Brosius

et al. 2021

IJMS

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Prader-Willi syndrome (PWS) is a neurogenetic multifactorial disorder caused by the deletion or inactivation of paternally imprinted genes on human chromosome 15q11-q13. The affected homologous locus is on mouse chromosome 7C. The positional conservation and organization of genes including the imprinting pattern between mice and men implies similar physiological functions of this locus. Therefore, considerable efforts to recreate the pathogenesis of PWS have been accomplished in mouse models. We provide a summary of different mouse models that were generated for the analysis of PWS and discuss their impact on our current understanding of corresponding genes, their putative functions and the pathogenesis of PWS. Murine models of PWS unveiled the contribution of each affected gene to this multi-facetted disease, and also enabled the establishment of the minimal critical genomic region (PWScr) responsible for core symptoms, highlighting the importance of non-protein coding genes in the PWS locus. Although the underlying disease-causing mechanisms of PWS remain widely unresolved and existing mouse models do not fully capture the entire spectrum of the human PWS disorder, continuous improvements of genetically engineered mouse models have proven to be very powerful and valuable tools in PWS research.

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Section: Snord116 Gene Clustermentioning

confidence: 99%

Section: Snord116 Gene Clustermentioning

confidence: 99%

A Comprehensive Review of Genetically Engineered Mouse Models for Prader-Willi Syndrome Research

Kummerfeld

Raabe

Brosius

et al. 2021

IJMS

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“…Multiple studies have also explored the role of Snord116 in hypothalamic regulation of hormones linked to diurnal behaviors. Orexin neurons in the hypothalamus facilitate sleep-wake cycles by regulating hormones that promote wakefulness (noradrenaline, histamine, and acetylcholine) and rest [melanine-concentrating hormone (MCH); Pace et al, 2020 ]. Loss of orexin neurons are widely implicated in dysregulated sleep in patients with narcolepsy and has been observed in patients with PWS as well ( Vgontzas et al, 1996 ; Chemelli et al, 1999 ; Mignot et al, 2002 ; Omokawa et al, 2016 ).…”

Section: Epigenetic Mechanisms In Pwsmentioning

confidence: 99%

“…Loss of orexin neurons are widely implicated in dysregulated sleep in patients with narcolepsy and has been observed in patients with PWS as well ( Vgontzas et al, 1996 ; Chemelli et al, 1999 ; Mignot et al, 2002 ; Omokawa et al, 2016 ). However, it was not until recently that loss of Snord116 was demonstrated to decrease orexin neuron levels in the lateral hypothalamus without altering levels of MCH and MCH neurons in mice ( Pace et al, 2020 ). A decrease in orexin neurons may facilitate the prolonged REM sleep characteristic of PWS due to the imbalance in orexin/MCH ratio with a higher MCH concentration during wake cycles promoting more rest ( Pace et al, 2020 ).…”

Section: Epigenetic Mechanisms In Pwsmentioning

confidence: 99%

“…However, it was not until recently that loss of Snord116 was demonstrated to decrease orexin neuron levels in the lateral hypothalamus without altering levels of MCH and MCH neurons in mice ( Pace et al, 2020 ). A decrease in orexin neurons may facilitate the prolonged REM sleep characteristic of PWS due to the imbalance in orexin/MCH ratio with a higher MCH concentration during wake cycles promoting more rest ( Pace et al, 2020 ). This phenomenon is not unique to Snord116 deletion mice, however, as this orexin/MCH imbalance was also observed in Magel2 deficient models ( Kozlov et al, 2007 ).…”

Section: Epigenetic Mechanisms In Pwsmentioning

confidence: 99%

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Epigenetics in Prader-Willi Syndrome

Mendiola

LaSalle

2021

Front. Genet.

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Prader-Willi Syndrome (PWS) is a rare neurodevelopmental disorder that affects approximately 1 in 20,000 individuals worldwide. Symptom progression in PWS is classically characterized by two nutritional stages. Stage 1 is hypotonia characterized by poor muscle tone that leads to poor feeding behavior causing failure to thrive in early neonatal life. Stage 2 is followed by the development of extreme hyperphagia, also known as insatiable eating and fixation on food that often leads to obesity in early childhood. Other major features of PWS include obsessive-compulsive and hoarding behaviors, intellectual disability, and sleep abnormalities. PWS is genetic disorder mapping to imprinted 15q11.2-q13.3 locus, specifically at the paternally expressed SNORD116 locus of small nucleolar RNAs and noncoding host gene transcripts. SNORD116 is processed into several noncoding components and is hypothesized to orchestrate diurnal changes in metabolism through epigenetics, according to functional studies. Here, we review the current status of epigenetic mechanisms in PWS, with an emphasis on an emerging role for SNORD116 in circadian and sleep phenotypes. We also summarize current ongoing therapeutic strategies, as well as potential implications for more common human metabolic and psychiatric disorders.

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