title: The disruption of Celf6, a gene identified by translational profiling of serotonergic neurons, results in autism-related behaviors.
abstract: The immense molecular diversity of neurons challenges our ability to understand the genetic and cellular etiology of neuropsychiatric disorders. Leveraging knowledge from neurobiology may help parse the genetic complexity: identifying genes important for a circuit that mediates a particular symptom of a disease may help identify polymorphisms that contribute to risk for the disease as a whole. The serotonergic system has long been suspected in disorders that have symptoms of repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit translational profiling of serotonergic neurons. From this, we identified several thousand serotonergic-cell expressed transcripts, of which 174 were highly enriched, including all known markers of these cells. Analysis of common variants near the corresponding genes in the AGRE collection implicated the RNA binding protein CELF6 in autism risk. Screening for rare variants in CELF6 identified an inherited premature stop codon in one of the probands. Subsequent disruption of Celf6 in mice resulted in animals exhibiting resistance to change and decreased ultrasonic vocalization as well as abnormal levels of serotonin in the brain. This work provides a reproducible and accurate method to profile serotonergic neurons under a variety of conditions and suggests a novel paradigm for gaining information on the etiology of psychiatric disorders.
authors: Department of Genetics and Psychiatry, Washington University School of Medicine, St. Louis, Missouri 63110, USA. jdougherty@genetics.wustl.edu
authors: Joseph D
authors: JD
authors: Dougherty
authors: Susan E
authors: SE
authors: Maloney
authors: David F
authors: DF
authors: Wozniak
authors: Michael A
authors: MA
authors: Rieger
authors: Lisa
authors: L
authors: Sonnenblick
authors: Giovanni
authors: G
authors: Coppola
authors: Nathaniel G
authors: NG
authors: Mahieu
authors: Juliet
authors: J
authors: Zhang
authors: Jinlu
authors: J
authors: Cai
authors: Gary J
authors: GJ
authors: Patti
authors: Brett S
authors: BS
authors: Abrahams
authors: Daniel H
authors: DH
authors: Geschwind
authors: Nathaniel
authors: N
authors: Heintz
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000235:genetics* / Q000523:psychology*; D001522:Behavior, Animal / Q000502:physiology; D000067878:CELF Proteins; D020869:Gene Expression Profiling / Q000379:methods*; D055106:Genome-Wide Association Study; D006801:Humans; D007150:Immunohistochemistry; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009154:Mutation / Q000235:genetics / Q000502:physiology; D018377:Neurotransmitter Agents / Q000378:metabolism; D011110:Polymorphism, Genetic; D046188:Protein Modification, Translational / Q000235:genetics* / Q000502:physiology*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D012270:Ribosomes / Q000235:genetics / Q000378:metabolism; D059326:Serotonergic Neurons / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D050486:Serotonin Plasma Membrane Transport Proteins / Q000235:genetics; D012903:Smell / Q000502:physiology; D012919:Social Behavior; D014828:Vocalization, Animal / Q000502:physiology
chemical_list: D000067878:CELF Proteins; C486465:CELF6 protein, human; D018377:Neurotransmitter Agents; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; D012701:Serotonin