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Cell-type specific utilization of multiple negative feedback loops generates developmental constancy.

机译:多个负反馈回路的细胞类型特异性利用产生发育恒定性。

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Signaling pathways generally contain multiple negative regulators that are induced by the signal they repress, constructing negative feedback loops. Although such negative regulators are often expressed in a tissue- or cell-type specific manner during development, little is known about the significance of their differential expression patterns and possible interactions. We show the role and interplay of two cell-type specific negative feedback loops during specification of photoreceptor neurons in the Drosophila compound eye, a process that occurs via epidermal growth factor (EGF)-mediated sequential induction through the activation of the Ras/MAPK signaling pathway. Inducing cells secreting EGF express a negative regulator Sprouty (SPRY) that lowers Ras/MAPK signaling activity, and as a consequence reduces the signal-dependent expression of a secreted EGF inhibitor, Argos (AOS). Induced cells in turn express an orphan nuclear receptor Seven-up (SVP), which represses SPRY expression thereby allowing expression and secretion of AOS, preventing further induction. When this intricate system fails, as in spry mutants, sequential induction is no longer constant and the number of photoreceptor neurons becomes variable. Thus, cell-type specific utilization of multiple negative feedback loops not only confers developmental robustness through functional redundancy, but is a key component in generating consistent patterning.
机译:信号通路通常包含多个负调节剂,这些信号由其抑制的信号诱导,从而构建了负反馈回路。尽管此类负调控因子通常在发育过程中以组织或细胞类型的特异性方式表达,但对其差异表达模式和可能相互作用的重要性知之甚少。我们展示了果蝇复合眼中感光神经元的规范过程中两个细胞类型特异性负反馈回路的作用和相互作用,该过程是通过激活Ras / MAPK信号传导通过表皮生长因子(EGF)介导的顺序诱导而发生的途径。分泌EGF的诱导细胞表达负调节剂Sprouty(SPRY),它降低了Ras / MAPK信号传导活性,因此降低了分泌的EGF抑制剂Argos(AOS)的信号依赖性表达。诱导的细胞依次表达孤核受体Seven-up(SVP),其抑制SPRY表达,从而表达和分泌AOS,从而阻止进一步诱导。当这种复杂的系统失效时,如在突变突变体中一样,顺序诱导不再是恒定的,并且感光神经元的数量也变得可变。因此,多个负反馈回路的特定于细胞类型的利用不仅通过功能冗余赋予了开发鲁棒性,而且是生成一致图案的关键组成部分。

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