The disruption of Celf6, a gene identified by translational profiling of serotonergic neurons, results in autism-related behaviors.
The disruption of Celf6, a gene identified by translational profiling of serotonergic neurons, results in autism-related behaviors.
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DOI：
10.1523/jneurosci.4762-12.2013
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发表时间：
2013-02-13
期刊：
影响因子：
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通讯作者：
Heintz N
中科院分区：
文献类型：
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作者：
Dougherty JD;Maloney SE;Wozniak DF;Rieger MA;Sonnenblick L;Coppola G;Mahieu NG;Zhang J;Cai J;Patti GJ;Abrahams BS;Geschwind DH;Heintz N
神经元巨大的分子多样性挑战了我们理解神经精神疾病的遗传和细胞病因的能力。利用神经生物学的知识可能有助于解析遗传复杂性：识别对介导疾病特定症状的回路重要的基因可能有助于识别导致疾病整体风险的多态性。长期以来，5 -羟色胺能系统一直被怀疑与重复性行为和抗拒改变的症状有关，包括自闭症。我们产生了一个bacTRAP小鼠系，以允许5 -羟色胺能神经元的翻译分析。由此，我们确定了数千个血清素能细胞表达转录本，其中174个是高度富集的，包括这些细胞的所有已知标记物。对AGRE收集的相应基因附近的常见变异的分析表明，RNA结合蛋白CELF6与自闭症风险有关。对CELF6的罕见变异进行筛查，在一个先证中发现了一个遗传性过早终止密码子。随后，小鼠体内Celf6的破坏导致动物表现出对变化的抵抗力，超声波发声减少，以及大脑中血清素水平异常。这项工作提供了一种可重复和准确的方法来分析各种条件下的血清素能神经元，并为获得精神疾病病因学信息提供了一种新的范例。
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.