Molecular cloning and functional analyses of a novel maternal neurogenic gene, neurotic that is essential for Notch signaling.

Notch信号从线虫到哺乳动物都是高度保守的，在许多发育过程中都起着关键作用。在果蝇胚胎中，Notch信号的缺乏会导致神经增生，通常被称为神经源性表型。在这里，我们鉴定了一个新的母体神经源性基因，Neurotic，并证明了它是Notch信号的关键，神经性编码一种与哺乳动物GDP-岩藻糖蛋白O-岩藻糖基转移酶高度同源的蛋白质，它将岩藻糖糖添加到表皮生长因子样的重复序列中。神经功能以细胞自主的方式进行，遗传感染试验表明，神经性是Notch全长但不是激活形式活动所必需的在果蝇培养细胞中，神经质对于β与其配体Delta的物理相互作用以及对这种相互作用的调节能力是必不可少的。我们在这里提供了一个前所未有的例子，绝对需要蛋白质糖基化事件来进行配体-受体的相互作用。我们的结果表明，神经质催化的O-岩藻糖化也参与了Notch的边缘非依赖性活动，并可能提供一种新的开关机制来调节连接和受体的相互作用。

Notch signalling, which is highly conserved from nematodes to mammals, plays critical roles in many developmental processes.In the Drosophila embryo, deficiency in Notch signalling results in neurohyperplasia, commonly referred to as the neurogenic phenotype.Here we identify a novel maternal neurogenic gene, neurotic, and show that it is essential for Notch signalling, neurotic encodes a protein highly homologous to mammalian GDP-fucose protein O-fucosyltransferase, which adds fucose sugar to epidermal growth factor-like repeats.neurotic functions in a cell autonomous manner, and genetic epistasis tests reveal that Neurotic is required for the activity of full-length but not an activated form of Notch.Further, we show that neurotic is required for Fringe activity, which encodes a fucose-specific,β1,3 N-acetylglucosaminyltransferase, previously shown to modulate Notch receptor activity.Finally, Neurotic is essential for the physical interaction of Notch with its ligand Delta, and for Fringe ability to modulate this interaction in Drosophila cultured cells.We present here an unprecedented example of an absolute requirement of a protein glycosylation event for a ligand-receptor interaction.Our results suggest,that O-fucosylation catalyzed by Neurotic is also involved in the Fringe-independent activities of Notch and may provide a novel on-off mechanism that regulates ligand-receptor interactions.