Cell-type specific utilization of multiple negative feedback loops generates developmental constancy
Cell-type specific utilization of multiple negative feedback loops generates developmental constancy
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DOI：
10.1111/j.1365-2443.2005.00871.x
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发表时间：
2005-07-01
期刊：
影响因子：
2.1
通讯作者：
Okabe, M
中科院分区：
文献类型：
--
作者：
Iwanami, M;Hiromi, Y;Okabe, M
信号通路通常包含多个负调节因子，这些负调节因子由它们抑制的信号诱导，构成负反馈环路。虽然这些负调控因子在发育过程中经常以组织或细胞类型特异性的方式表达，但人们对它们的差异表达模式和可能的相互作用的重要性知之甚少。我们展示了两个细胞型的特定负反馈环在果蝇复眼中光感受器神经元的指定过程中的作用和相互作用，这一过程通过激活Ras/MAPK信号通路，通过表皮生长因子(EGF)介导的顺序诱导发生。诱导分泌EGF的细胞表达负调控因子Sprouty(SPRY)，降低Ras/MAPK信号活性，从而减少分泌EGF抑制物Argos(AOS)的信号依赖性表达。被诱导的细胞反过来表达一种孤儿核受体S7-UP(SVP)，它抑制SPRY的表达，从而允许AOS的表达和分泌，从而阻止进一步的诱导。当这个错综复杂的系统失效时，就像在SPRY突变体中一样，顺序诱导不再是恒定的，光感受器神经元的数量变得可变。因此，多个负反馈环的细胞类型特异性利用不仅通过功能冗余赋予发育稳健性，而且是产生一致模式的关键组成部分。
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.