The Disruption of Celf6, a Gene Identified by Translational Profiling of Serotonergic Neurons, Results in Autism-related Behaviors

Overview

Journal J Neurosci

Specialty Neurology

Date 2013 Feb 15

PMID 23407934

Citations 56

Authors

Joseph D Dougherty

Susan E Maloney

David F Wozniak

Michael A Rieger

Lisa Sonnenblick

Giovanni Coppola

Nathaniel G Mahieu

Juliet Zhang

Jinlu Cai

Gary J Patti

Brett S Abrahams

Daniel H Geschwind

Nathaniel Heintz

Affiliations

Soon will be listed here.

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.

Citing Articles

Perinatal oxycodone exposure causes long-term sex-dependent changes in weight trajectory and sensory processing in adult mice.

Minakova E, Mikati M, Madasu M, Conway S, Baldwin J, Swift R Psychopharmacology (Berl). 2022; 239(12):3859-3873.

PMID: 36269379 DOI: 10.1007/s00213-022-06257-8.

Advanced paternal age diversifies individual trajectories of vocalization patterns in neonatal mice.

Mai L, Inada H, Kimura R, Kanno K, Matsuda T, Tachibana R iScience. 2022; 25(8):104834.

PMID: 36039363 PMC: 9418688. DOI: 10.1016/j.isci.2022.104834.

Evolution of the Neocortex Through RNA-Binding Proteins and Post-transcriptional Regulation.

Salamon I, Rasin M Front Neurosci. 2022; 15:803107.

PMID: 35082597 PMC: 8784817. DOI: 10.3389/fnins.2021.803107.

A MYT1L syndrome mouse model recapitulates patient phenotypes and reveals altered brain development due to disrupted neuronal maturation.

Chen J, Lambo M, Ge X, Dearborn J, Liu Y, McCullough K Neuron. 2021; 109(23):3775-3792.e14.

PMID: 34614421 PMC: 8668036. DOI: 10.1016/j.neuron.2021.09.009.

Rare and de novo variants in 827 congenital diaphragmatic hernia probands implicate LONP1 as candidate risk gene.

Qiao L, Xu L, Yu L, Wynn J, Hernan R, Zhou X Am J Hum Genet. 2021; 108(10):1964-1980.

PMID: 34547244 PMC: 8546037. DOI: 10.1016/j.ajhg.2021.08.011.

References

Doyle J, Dougherty J, Heiman M, Schmidt E, Stevens T, Ma G . Application of a translational profiling approach for the comparative analysis of CNS cell types. Cell. 2008; 135(4):749-62. PMC: 2763427. DOI: 10.1016/j.cell.2008.10.029. View

Holy T, Guo Z . Ultrasonic songs of male mice. PLoS Biol. 2005; 3(12):e386. PMC: 1275525. DOI: 10.1371/journal.pbio.0030386. View

Schaefer M, Wong S, Wozniak D, Muglia L, Liauw J, Zhuo M . Altered stress-induced anxiety in adenylyl cyclase type VIII-deficient mice. J Neurosci. 2000; 20(13):4809-20. PMC: 6772287. View

Hollander E, Soorya L, Chaplin W, Anagnostou E, Taylor B, Ferretti C . A double-blind placebo-controlled trial of fluoxetine for repetitive behaviors and global severity in adult autism spectrum disorders. Am J Psychiatry. 2011; 169(3):292-9. DOI: 10.1176/appi.ajp.2011.10050764. View

Charlet-B N, Logan P, Singh G, Cooper T . Dynamic antagonism between ETR-3 and PTB regulates cell type-specific alternative splicing. Mol Cell. 2002; 9(3):649-58. DOI: 10.1016/s1097-2765(02)00479-3. View

Silverman J, Turner S, Barkan C, Tolu S, Saxena R, Hung A . Sociability and motor functions in Shank1 mutant mice. Brain Res. 2010; 1380:120-37. PMC: 3041833. DOI: 10.1016/j.brainres.2010.09.026. View

Goridis C, Rohrer H . Specification of catecholaminergic and serotonergic neurons. Nat Rev Neurosci. 2002; 3(7):531-41. DOI: 10.1038/nrn871. View

Pobbe R, Pearson B, Defensor E, Bolivar V, Young 3rd W, Lee H . Oxytocin receptor knockout mice display deficits in the expression of autism-related behaviors. Horm Behav. 2011; 61(3):436-44. PMC: 3373312. DOI: 10.1016/j.yhbeh.2011.10.010. View

ORoak B, Vives L, Girirajan S, Karakoc E, Krumm N, Coe B . Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012; 485(7397):246-50. PMC: 3350576. DOI: 10.1038/nature10989. View

10.

McClellan J, King M . Genetic heterogeneity in human disease. Cell. 2010; 141(2):210-7. DOI: 10.1016/j.cell.2010.03.032. View

11.

Neale B, Kou Y, Liu L, Maayan A, Samocha K, Sabo A . Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature. 2012; 485(7397):242-5. PMC: 3613847. DOI: 10.1038/nature11011. View

12.

Cook Jr E, Courchesne R, Lord C, Cox N, Yan S, Lincoln A . Evidence of linkage between the serotonin transporter and autistic disorder. Mol Psychiatry. 1997; 2(3):247-50. DOI: 10.1038/sj.mp.4000266. View

13.

Happe F, Ronald A . The 'fractionable autism triad': a review of evidence from behavioural, genetic, cognitive and neural research. Neuropsychol Rev. 2008; 18(4):287-304. DOI: 10.1007/s11065-008-9076-8. View

14.

Nakatani J, Tamada K, Hatanaka F, Ise S, Ohta H, Inoue K . Abnormal behavior in a chromosome-engineered mouse model for human 15q11-13 duplication seen in autism. Cell. 2009; 137(7):1235-46. PMC: 3710970. DOI: 10.1016/j.cell.2009.04.024. View

15.

Sunyaev S, Ramensky V, Koch I, Lathe 3rd W, Kondrashov A, Bork P . Prediction of deleterious human alleles. Hum Mol Genet. 2001; 10(6):591-7. DOI: 10.1093/hmg/10.6.591. View

16.

Wozniak D, Hartman R, Boyle M, Vogt S, Brooks A, Tenkova T . Apoptotic neurodegeneration induced by ethanol in neonatal mice is associated with profound learning/memory deficits in juveniles followed by progressive functional recovery in adults. Neurobiol Dis. 2004; 17(3):403-14. DOI: 10.1016/j.nbd.2004.08.006. View

17.

Deneris E, Wyler S . Serotonergic transcriptional networks and potential importance to mental health. Nat Neurosci. 2012; 15(4):519-27. PMC: 3594782. DOI: 10.1038/nn.3039. View

18.

McDougle C, Naylor S, Cohen D, Aghajanian G, Heninger G, Price L . Effects of tryptophan depletion in drug-free adults with autistic disorder. Arch Gen Psychiatry. 1996; 53(11):993-1000. DOI: 10.1001/archpsyc.1996.01830110029004. View

19.

Bucan M, Abrahams B, Wang K, Glessner J, Herman E, Sonnenblick L . Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes. PLoS Genet. 2009; 5(6):e1000536. PMC: 2695001. DOI: 10.1371/journal.pgen.1000536. View

20.

Yuhas J, Cordeiro L, Tassone F, Ballinger E, Schneider A, Long J . Brief report: Sensorimotor gating in idiopathic autism and autism associated with fragile X syndrome. J Autism Dev Disord. 2010; 41(2):248-53. PMC: 3023021. DOI: 10.1007/s10803-010-1040-9. View