Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.
Nat Neurosci. 2012 Feb 26;15(4):519-27. doi: 10.1038/nn.3039.
Transcription regulatory networks governing the genesis, maturation and maintenance of vertebrate brain serotonin (5-HT) neurons determine the level of serotonergic gene expression and signaling throughout an animal's lifespan. Recent studies suggest that alterations in these networks can cause behavioral and physiological pathogenesis in mice. Here, we synthesize findings from vertebrate loss-of-function and gain-of-function studies to build a new model of the transcriptional regulatory networks that specify 5-HT neurons during fetal life, integrate them into CNS circuitry in early postnatal life and maintain them in adulthood. We then describe findings from animal and human genetic studies that support possible alterations in the activity of serotonergic regulatory networks in the etiology of mental illness. We conclude with a discussion of the potential utility of our model, as an experimentally well-defined molecular pathway, to predict and interpret the biological effect of genetic variation that may be discovered in the orthologous human network.
转录调控网络调控脊椎动物大脑中血清素（5-HT）神经元的发生、成熟和维持，决定了动物整个生命周期中血清素能基因表达和信号转导的水平。最近的研究表明，这些网络的改变可能导致小鼠的行为和生理发病机制。在这里，我们综合了脊椎动物功能丧失和功能获得研究的结果，构建了一个新的转录调控网络模型，该模型在胎儿期特异性指定 5-HT 神经元，并在出生后早期将其整合到中枢神经系统回路中，并在成年期维持其功能。然后，我们描述了来自动物和人类遗传研究的结果，这些结果支持在精神疾病的发病机制中，可能存在 5-HT 能调节网络活性的改变。最后，我们讨论了我们的模型作为一个实验定义明确的分子途径的潜在应用价值，以预测和解释可能在同源人类网络中发现的遗传变异的生物学效应。
