Baker N E, Yu S, Han D
Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Curr Biol. 1996 Oct 1;6(10):1290-301. doi: 10.1016/s0960-9822(02)70715-x.
Receptors of the Notch family affect the determination of many cell types. In the Drosophila eye, Notch antagonises the basic helix-loop-helix (bHLH) protein atonal, which is required for R8 photoreceptor determination. Similar antagonism between Notch and proneural bHLH proteins regulates most neural cell determination, however, it is uncertain whether the mechanisms are similar in all cases. Here, we have analyzed the sensitivity of atonal expression to Notch signalling using a temperature-sensitive Notch allele, by the expression of activated Notch or of the ligand Serrate, and by monitoring expression of the atonal-dependant gene scabrous and of the Notch-dependent Enhancer of split genes.
The atonal expression pattern evolves from general "prepattern' expression, through transient "intermediate groups' to R8 precursor-specific expression. Successive phases of atonal expression differ in sensitivity to Notch. Prepattern expression of atonal is not inhibited. Inhibition begins at the intermediate group stage, corresponding to the period when atonal gene function is required for its own expression. At the transition to R8 cell-specific expression, Notch is activated in all intermediate group cells except the R8 cell precursor. R8 cells remain sensitive to inhibition in columns 0 and 1, but become less sensitive thereafter; non-R8 cells do not require Notch activity to keep atonal expression inactive. Thus, Notch signaling is coupled to atonal repression for only part of the atonal expression pattern. Accordingly, the Enhancer-of-split m delta protein is expressed reciprocally to atonal at the intermediate group and early R8 stages, but is expressed in other patterns before and after.
In eye development, inhibition by Notch activity is restricted to specific phases of proneural gene expression, beginning when prepattern decays and is replaced by autoregulation. We suggest that Notch signalling inhibits atonal autoregulation, but not expression by other mechanisms, and that a transition from prepattern to autoregulation is necessary for patterning neural cell determination. Distinct neural tissues might differ in their proneural prepatterns, but use Notch in a similar mechanism.
Notch家族受体影响多种细胞类型的决定。在果蝇眼睛中，Notch拮抗碱性螺旋-环-螺旋（bHLH）蛋白无调性，而无调性是R8光感受器决定所必需的。Notch与原神经bHLH蛋白之间的类似拮抗作用调节大多数神经细胞的决定，然而，尚不确定所有情况下机制是否相似。在这里，我们使用温度敏感的Notch等位基因、通过激活的Notch或配体锯齿蛋白的表达以及通过监测无调性依赖基因粗糙和Notch依赖的分裂增强子基因的表达，分析了无调性表达对Notch信号的敏感性。
无调性表达模式从一般的“前模式”表达，经过短暂的“中间组”，发展为R8前体特异性表达。无调性表达的连续阶段对Notch的敏感性不同。无调性的前模式表达不受抑制。抑制在中间组阶段开始，这与无调性基因功能对其自身表达是必需的时期相对应。在向R8细胞特异性表达转变时，除R8细胞前体之外的所有中间组细胞中Notch被激活。R8细胞在第0列和第1列中对抑制仍敏感，但此后变得不那么敏感；非R8细胞不需要Notch活性来保持无调性表达失活。因此，Notch信号仅在无调性表达模式的一部分中与无调性抑制相关联。相应地，分裂增强子mδ蛋白在中间组和早期R8阶段与无调性呈反向表达，但在之前和之后以其他模式表达。
在眼睛发育中，Notch活性的抑制仅限于原神经基因表达的特定阶段，始于前模式衰退并被自动调节取代之时。我们认为，Notch信号抑制无调性自动调节，但不抑制其他机制的表达，并且从前模式到自动调节的转变对于神经细胞决定模式化是必要的。不同的神经组织可能在其原神经前模式上有所不同，但以类似机制利用Notch。
