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

Notch信号在线虫和哺乳动物中高度保守，在许多发育过程中起着至关重要的作用。在果蝇胚胎中，Notch信号的缺乏导致神经增生，通常被称为神经源性表型。在这里，我们发现了一个新的母体神经源性基因，neurotic，并表明它对Notch信号至关重要，neurotic编码一种与哺乳动物GDP-聚焦蛋白O-聚焦转移酶高度同源的蛋白质，该蛋白将聚焦糖添加到表皮生长因子样重复序列中。neurotic以细胞自主的方式发挥功能，遗传上位性测试表明，neurotic是全长Notch的活性所必需的，而不是激活形式的Notch。此外，我们表明，边缘活性需要神经症，它编码一种聚焦特异性的β1,3 n -乙酰氨基葡萄糖转移酶，该酶先前被证明可以调节Notch受体活性。最后，Neurotic对于Notch与其配体Delta的物理相互作用以及在果蝇培养细胞中调节这种相互作用的Fringe能力至关重要。我们在这里提出了一个前所未有的例子，一个蛋白质糖基化事件的配体-受体相互作用的绝对要求。我们的研究结果表明，由Neurotic催化的O-聚焦化也参与了Notch的边缘非依赖性活动，并可能提供一种调节配体-受体相互作用的新型开关机制。

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.