Laboratory of Genetics, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
Neuron. 2011 Dec 22;72(6):964-76. doi: 10.1016/j.neuron.2011.12.003.
In a forward genetic screen in Drosophila, we have isolated insomniac, a mutant that severely reduces the duration and consolidation of sleep. Anatomically restricted genetic manipulations indicate that insomniac functions within neurons to regulate sleep. insomniac expression does not oscillate in a circadian manner, and conversely, the circadian clock is intact in insomniac mutants, suggesting that insomniac regulates sleep by pathways distinct from the circadian clock. The protein encoded by insomniac is a member of the BTB/POZ superfamily, which includes many proteins that function as adaptors for the Cullin-3 (Cul3) ubiquitin ligase complex. We show that Insomniac can physically associate with Cul3, and that reduction of Cul3 activity in neurons recapitulates the insomniac phenotype. The extensive evolutionary conservation of insomniac and Cul3 suggests that protein degradation pathways may have a general role in governing the sleep and wakefulness of animals.
在果蝇的正向遗传筛选中，我们分离出了失眠突变体，该突变体严重缩短了睡眠的持续时间和巩固时间。在解剖上受限的遗传操作表明，失眠突变体在神经元内发挥作用以调节睡眠。失眠突变体中的表达不以昼夜节律的方式波动，相反，生物钟在失眠突变体中是完整的，这表明失眠突变体通过与生物钟不同的途径来调节睡眠。失眠突变体编码的蛋白是 BTB/POZ 超家族的成员，该超家族包括许多作为 Cullin-3（Cul3）泛素连接酶复合物的衔接蛋白的蛋白。我们表明，Insomniac 可以与 Cul3 发生物理关联，并且神经元中 Cul3 活性的降低再现了失眠表型。Insomniac 和 Cul3 的广泛进化保守性表明，蛋白质降解途径可能在调节动物的睡眠和觉醒方面具有普遍作用。
