Li Y, Baker N E
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Curr Biol. 2001 Mar 6;11(5):330-8. doi: 10.1016/s0960-9822(01)00093-8.
The receptor protein Notch plays a conserved role in restricting neural-fate specification during lateral inhibition. Lateral inhibition requires the Notch intracellular domain to coactivate Su(H)-mediated transcription of the Enhancer-of-split Complex. During Drosophila eye development, Notch plays an additional role in promoting neural fate independently of Su(H) and E(spl)-C, and this finding suggests an alternative mechanism of Notch signal transduction.
We used genetic mosaics to analyze the proneural enhancement pathway. As in lateral inhibition, the metalloprotease Kuzbanian, the EGF repeat 12 region of the Notch extracellular domain, Presenilin, and the Notch intracellular domain were required. By contrast, proneural enhancement became constitutive in the absence of Su(H), and this led to premature differentiation and upregulation of the Atonal and Senseless proteins. Ectopic Notch signaling by Delta expression ahead of the morphogenetic furrow also caused premature differentiation.
Proneural enhancement and lateral inhibition use similar ligand binding and receptor processing but differ in the nuclear role of Su(H). Prior to Notch signaling, Su(H) represses neural development directly, not indirectly through E(spl)-C. During proneural enhancement, the Notch intracellular domain overcomes the repression of neural differentiation. Later, lateral inhibition restores the repression of neural development by a different mechanism, requiring E(spl)-C transcription. Thus, Notch restricts neurogenesis temporally to a narrow time interval between two modes of repression.
受体蛋白Notch在侧向抑制过程中对限制神经命运特化发挥着保守作用。侧向抑制需要Notch胞内结构域共同激活由Su(H)介导的分裂增强复合体的转录。在果蝇眼睛发育过程中，Notch在独立于Su(H)和E(spl)-C的情况下对促进神经命运发挥额外作用，这一发现提示了一种Notch信号转导的替代机制。
我们利用遗传镶嵌体分析神经原增强途径。与侧向抑制一样，金属蛋白酶库兹班尼亚、Notch胞外结构域的表皮生长因子重复序列12区域、早老素和Notch胞内结构域是必需的。相比之下，在缺乏Su(H)的情况下神经原增强变为组成型，这导致过早分化以及无调性蛋白和无意义蛋白的上调。在形态发生沟前方通过Delta表达进行的异位Notch信号传导也导致过早分化。
神经原增强和侧向抑制使用相似的配体结合和受体加工方式，但在Su(H)的核作用方面存在差异。在Notch信号传导之前，Su(H)直接抑制神经发育，而非通过E(spl)-C间接抑制。在神经原增强过程中，Notch胞内结构域克服对神经分化的抑制。之后，侧向抑制通过一种不同的机制恢复对神经发育的抑制，这需要E(spl)-C转录。因此，Notch将神经发生暂时限制在两种抑制模式之间的狭窄时间间隔内。
