Lateral inhibition in proneural clusters: cis-regulatory logic and default repression by Suppressor of Hairless
Lateral inhibition in proneural clusters: cis-regulatory logic and default repression by Suppressor of Hairless
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DOI：
10.1242/dev.01920
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发表时间：
2005-08-01
期刊：
影响因子：
4.6
通讯作者：
Posakony, JW
中科院分区：
文献类型：
--
作者：
Castro, B;Barolo, S;Posakony, JW
侧向抑制，其中单个细胞向其邻居发出信号以防止它们采用自己的命运，是通过Notch（N）途径进行细胞间通信的最知名的设置。在果蝇的外周神经发生过程中，感觉器官前体（SOP）细胞出现在前神经簇（PNC）中，这些细胞通过表达前神经转录激活因子而具有SOP命运潜能。SOP使用N信号在邻近的PNC细胞中激活抑制SOP命运的多个基因的表达。这些基因在转录上响应于前神经蛋白和无毛N途径转录因子抑制因子[Su（H）]的直接调节，并且它们的激活通常是高度不对称的;即仅在PNC的受抑制（非SOP）细胞中，而不在SOP中。我们发现，SOP中显著较高的前神经蛋白水平使该细胞处于不适当地激活SOP抑制基因的风险中，即使没有来自N-激活的Su（H）的输入。我们证明，这是通过Su（H）对这些基因的直接“默认”抑制来防止的，Su（H）通过与非SOP中用于激活的结合位点相同的结合位点起作用。我们表明，即使是一个单一的N途径靶基因的SOP去阻遏可以消灭SOP细胞的命运。最后，我们定义了衔接蛋白Hairless和辅助阻遏物Groucho和CtBP在SOP中对Su（H）赋予阻遏活性的关键作用。我们的工作阐明了N信号和前神经蛋白合作，创造神经前体/表皮细胞的命运区别在侧抑制的监管逻辑。
Lateral inhibition, wherein a single cell signals to its neighbors to prevent them from adopting its own fate, is the best-known setting for cell-cell communication via the Notch (N) pathway. During peripheral neurogenesis in Drosophila, sensory organ precursor (SOP) cells arise within proneural clusters (PNCs), small groups of cells endowed with SOP fate potential by their expression of proneural transcriptional activators. SOPs use N signaling to activate in neighboring PNC cells the expression of multiple genes that inhibit the SOP fate. These genes respond transcriptionally to direct regulation by both the proneural proteins and the N pathway transcription factor Suppressor of Hairless [Su(H)], and their activation is generally highly asymmetric; i.e. only in the inhibited (non-SOP) cells of the PNC, and not in SOPs. We show that the substantially higher proneural protein levels in the SOP put this cell at risk of inappropriately activating the SOP-inhibitory genes, even without input from N-activated Su(H). We demonstrate that this is prevented by direct 'default' repression of these genes by Su(H), acting through the same binding sites it uses for activation in non-SOPs. We show that de-repression of even a single N pathway target gene in the SOP can extinguish the SOP cell fate. Finally, we define crucial roles for the adaptor protein Hairless and the co-repressors Groucho and CtBP in conferring repressive activity on Su(H) in the SOP. Our work elucidates the regulatory logic by which N signaling and the proneural proteins cooperate to create the neural precursor/epidermal cell fate distinction during lateral inhibition.