Walters James W, Muñoz Claudia, Paaby Annalise B, Dinardo Stephen
Weill Graduate School of Medical Sciences, New York, NY 10021, USA.
Dev Biol. 2005 Oct 15;286(2):415-26. doi: 10.1016/j.ydbio.2005.06.031. Epub 2005 Aug 24.
The Drosophila embryonic epidermis has been a key model for understanding the establishment of cell type diversity across a cellular field. During segmental patterning, distinct signaling territories are established that employ either the Hedgehog, Spitz, Serrate or Wingless ligands. How these pathways control segmental pattern is not completely clear. One major decision occurs as cells are allocated to differentiate either smooth cuticle or denticle type cuticle. This allocation is based on competition between Wingless signaling and Spitz, which activates the Epidermal Growth Factor Receptor (EGFR). Here we show that a main role for Serrate-Notch signaling is to adjust the Spitz signaling domain. Serrate accomplishes this task by activating Notch in a discrete domain, the main purpose of which is to broaden the spatially regulated expression of Rhomboid. This adjusts the breadth of the source for Spitz, since Rhomboid is necessary for the production of active Spitz. We also show that the Serrate antagonist, fringe, must temper Notch activity to insure that the activation of the EGFR is not too robust. Together, Serrate and Fringe modulate Notch activation to generate the proper level of EGFR activation. If Serrate-Notch signaling is absent, the denticle field narrows while the smooth cell field expands, as judged by the expression of the denticle field determinant Ovo/Shaven baby. This establishes one important role for the Serrate signaling territory, which is to define the extent of denticle field specification.
果蝇胚胎表皮一直是理解细胞类型在细胞区域内多样性建立的关键模型。在节段模式形成过程中，会建立起不同的信号区域，这些区域使用刺猬蛋白（Hedgehog）、斯皮茨蛋白（Spitz）、锯齿蛋白（Serrate）或无翅蛋白（Wingless）配体。这些信号通路如何控制节段模式尚不完全清楚。一个主要的决定发生在细胞被分配去分化为光滑表皮或齿状表皮类型时。这种分配基于无翅信号和激活表皮生长因子受体（EGFR）的斯皮茨蛋白之间的竞争。在这里我们表明，锯齿-Notch信号的一个主要作用是调整斯皮茨信号域。锯齿蛋白通过在一个离散区域激活Notch来完成这项任务，其主要目的是扩大菱形蛋白（Rhomboid）在空间上受调控的表达。这调整了斯皮茨蛋白的来源范围，因为菱形蛋白对于活性斯皮茨蛋白的产生是必需的。我们还表明，锯齿蛋白拮抗剂边缘蛋白（fringe）必须调节Notch活性，以确保EGFR的激活不会过于强烈。总之，锯齿蛋白和边缘蛋白调节Notch激活，以产生适当水平的EGFR激活。如果缺乏锯齿-Notch信号，根据齿状区域决定因子Ovo/无毛宝宝（Ovo/Shaven baby）的表达判断，齿状区域会变窄，而光滑细胞区域会扩大。这确立了锯齿信号区域的一个重要作用，即确定齿状区域特化的范围。
