title: Increased alternate splicing of Htr2c in a mouse model for Prader-Willi syndrome leads disruption of 5HT2Creceptor mediated appetite.
abstract: Alternate splicing of serotonin (5-hydroxytryptamine; 5-HT) 2C receptor (5-HT2CR) pre-RNA is negatively regulated by the small nucleolar RNA, Snord115, loss of which is observed in nearly all individuals with Prader-Willi Syndrome (PWS), a multigenic disorder characterised by hyperphagia and obesity. Given the role of the 5-HT2CR in the regulation of ingestive behaviour we investigated the pathophysiological implications of Snord115 deficiency on 5-HT2CR regulated appetite in a genotypically relevant PWS mouse model (PWS-IC). Specifically, we demonstrate that loss of Snord115 expression is associated with increased levels of hypothalamic truncated 5-HT2CR pre-mRNA. The 5-HT2CR promotes appetite suppression via engagement of the central melanocortin system. Pro-opiomelancortin (Pomc) mRNA levels within the arcuate nucleus of the hypothalamus (ARC) were reduced in PWS-IC mice. We then went on to assess the functional consequences of these molecular changes, demonstrating that PWS-IC mice are unresponsive to an anorectic doses of a 5-HT2CR agonist and that this is associated with attenuated activation of POMC neurons within the ARC. These data provide new insight into the significance of Htr2c pre-mRNA processing to the physiological regulation of appetite and potentially the pathological manifestation of hyperphagia in PWS. Furthermore, these findings have translational relevance for individuals with PWS who may seek to control appetite with another 5-HT2CR agonist, the new obesity treatment lorcaserin.
authors.affiliation: Centre for Integrative Physiology, University of Edinburgh, Edinburgh, UK.|Present address: Cardiovascular and Metabolic Disease, Pfizer, Cambridge, MA, 02139, USA.
authors.forename: Alastair S
authors.initials: AS
authors.lastname: Garfield
authors.affiliation: Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine and Pscyhology, Cardiff University, Cardiff, UK.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Davies
authors.affiliation: Department of Pharmacology, University of Cambridge, Cambridge, UK.
authors.forename: Luke K
authors.initials: LK
authors.lastname: Burke
authors.affiliation: Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine and Pscyhology, Cardiff University, Cardiff, UK.
authors.forename: Hannah V
authors.initials: HV
authors.lastname: Furby
authors.affiliation: Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine and Pscyhology, Cardiff University, Cardiff, UK.
authors.forename: Lawrence S
authors.initials: LS
authors.lastname: Wilkinson
authors.affiliation: Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, UK.
authors.forename: Lora K
authors.initials: LK
authors.lastname: Heisler
authors.affiliation: Behavioural Genetics Group, MRC Centre for Neuropsychiatric Genetics and Genomics, Neuroscience and Mental Health Research Institute, Schools of Medicine and Pscyhology, Cardiff University, Cardiff, UK. IslesAR1@cardiff.ac.uk.
authors.forename: Anthony R
authors.initials: AR
authors.lastname: Isles
mesh_terms: D017398:Alternative Splicing / Q000235:genetics*; D000818:Animals; D000855:Anorexia / Q000235:genetics / Q000473:pathology; D001066:Appetite / Q000235:genetics*; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D004195:Disease Models, Animal; D005247:Feeding Behavior; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011218:Prader-Willi Syndrome / Q000235:genetics* / Q000473:pathology; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D044405:Receptor, Serotonin, 5-HT2C / Q000235:genetics* / Q000378:metabolism; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology
chemical_list: C502777:8,9-dichloro-2,3,4,4a-tetrahydro-1H-pyrazino(1,2-a)quinoxalin-5(6H)-one; D050505:Mutant Proteins; D016760:Proto-Oncogene Proteins c-fos; D011719:Pyrazines; D011810:Quinoxalines; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D011333:Pro-Opiomelanocortin
keywords: Alternate splicing; Feeding; Prader-Willi syndrome; Serotonin 2C recptor; Snord115