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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 deconvolve the relationship between the genetic and the cellular underpinnings of neuropsychiatric disorders. We suspected that comprehensive approaches to parsing this complexity may inform human genetics studies. The serotonergic system has long been suspected in disorders that involve repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit the in vivo profiling of all ongoing translation in serotonergic neurons. From this, we identified 174 serotonergic-cell enriched and specific genes, including all known markers of these cells. Analysis of common variants in these genes in human families with autism implicated two genes, C1QTNF2 and the RNA-binding protein CELF6. This work provides a reproducible and accurate method to assess the translational profiles of serotonergic neurons under a variety of conditions in vivo, and suggests cell-specific information may provide some insight into the genetic etiology of complex psychiatric disorders

ORGANISM(S): Mus musculus

PROVIDER: GSE36068 | GEO | 2012/12/31

SECONDARY ACCESSION(S): PRJNA151825

REPOSITORIES: GEO

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

Project description:The immense molecular diversity of neurons challenges our ability to deconvolve the relationship between the genetic and the cellular underpinnings of neuropsychiatric disorders. We suspected that comprehensive approaches to parsing this complexity may inform human genetics studies. The serotonergic system has long been suspected in disorders that involve repetitive behaviors and resistance to change, including autism. We generated a bacTRAP mouse line to permit the in vivo profiling of all ongoing translation in serotonergic neurons. From this, we identified 174 serotonergic-cell enriched and specific genes, including all known markers of these cells. Analysis of common variants in these genes in human families with autism implicated two genes, C1QTNF2 and the RNA-binding protein CELF6. This work provides a reproducible and accurate method to assess the translational profiles of serotonergic neurons under a variety of conditions in vivo, and suggests cell-specific information may provide some insight into the genetic etiology of complex psychiatric disorders For each cell population, three independent TRAP replicates were collected, and total RNA from both the immunoprecipitate and unbound fractions were seperately amplified and hybridized. For each tissue, several representative unnbound fractions are provided to serve as controls. Biological replicates are GCRMA normalized within groups. Following averaging of replicates, we recommend further global normalization between groups, using affymetrix biotinylated controls, to correct for any broad biases in scanning and hybridization. Finally for many analyses, we also recommend filtering to remove those probesets with low IP/UB fold change values from each cell type(see PMID:20962086). Researchers can contact us for spreadsheets where these additional steps have been completed.

2012-12-31 | E-GEOD-36068 | biostudies-arrayexpress

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Project description:Mental disorders are caused by genetic and environmental factors. We here show that deficiency of an isoform of dopamine D2 receptor (D2R), D2LR, causes psychosocial stress vulnerability in mouse. This occurs through dysfunction of type 1A serotonin (5-hydroxytryptamine, 5-HT) receptor (5-HT1AR) on serotonergic neurons in the mouse brain. Exposure to forced swim stress significantly increased anxiety- and depressive-like behaviors in D2LR knockout (D2LR-KO) male mice as compared with wild-type mice. Treatment with 8-OH-DPAT, a 5-HT1AR agonist, failed to alleviate the stress-induced behaviors in D2LR-KO mice. In forced swim-stressed D2LR-KO mice, 5-HT release in the medial prefrontal cortex was elevated and the expression of genes related to 5-HT levels was up-regulated by the transcription factor PET1 in the dorsal raphe nucleus. Notably, D2LR formed a heteromer with 5-HT1AR in serotonergic neurons, thereby suppressing 5-HT1AR–activated G-protein–activated inwardly rectifying potassium (GIRK) conductance in D2LR-KO serotonergic neurons. Finally, D2LR overexpression in serotonergic neurons in the dorsal raphe nucleus alleviated stress vulnerability observed in D2LR-KO mice. Taken together, we conclude that disruption of the negative feedback regulation by the D2LR/5-HT1A heteromer causes stress vulnerability.

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Project description:Performed RNA-seq analysis of animals with xbp-1s overexpression (ER stress response transcription factor) in specific neuron types: pan-neuronal, serotonergic neuron, dopaminergic neuron, and both serotonergic and dopaminergic neurons, all compared to a wild-type control. RNA-seq was performed on purified RNA extracted from ~1000 whole worms using a proprietary Genewiz protocol described briefly in the manuscript. 3 biological replicates are provided for each sample.

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Transcriptional profiling of human serotonergic neurons in vitro

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Translational profiling of hypocretin neurons identifies Lhx9 as necessary for normal development of the hypocretinergic system.

Project description:The immense molecular diversity of neurons challenges our ability to deconvolve the relationship between the genetic and the cellular underpinnings of neuropsychiatric disorders. Hypocretin (orexin) containing neurons of the lateral hypothalamus are clearly essential for the normal regulation of sleep and wake behaviors, and have been implicated in feeding, anxiety, depression and reward. However, little is known about the molecular phenotypes of these cells, or the mechanism of their specification. We have generated a Hcrt bacTRAP line for comprehensive translational profiling of these neurons in vivo. From this profile, we have identified 188 transcripts, as enriched in these neurons, in additions to thousands more moderately enriched or nominally expressed. We validated many of these at the RNA and protein level, including the transcription factor Lhx9. Lhx9 protein is found in a subset of these neurons, and ablation of these gene results in a 30% loss of Hcrt neuron number, and a profound hypersomnolence in mice. This data suggests that Lhx9 may be important for specification of some Hcrt neurons, and the subsets of these neurons may contribute to discrete sleep phenotypes.

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Next Generation Sequencing of zebrafish intraspinal serotonergic neurons in the injury segment and distal segments after spinal cord injury

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