Antagonistic Feedback Loops Involving Rau and Sprouty in the Drosophila Eye Control Neuronal and Glial Differentiation
Antagonistic Feedback Loops Involving Rau and Sprouty in the Drosophila Eye Control Neuronal and Glial Differentiation
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DOI：
10.1126/scisignal.2004651
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发表时间：
2013-11-05
影响因子：
7.3
通讯作者：
Klaembt, Christian
中科院分区：
文献类型：
--
作者：
Sieglitz, Florian;Matzat, Till;Klaembt, Christian
在发育过程中，分化通常是通过激活不同的受体酪氨酸激酶(RTK)来启动的，这导致了细胞质信号级联的严格调控激活。在发育中的果蝇眼的神经元和神经胶质细胞的分化过程中，我们发现，在成纤维细胞生长因子受体(FGFR)或表皮生长因子受体下游，适当强度的RTK信号需要两个相互拮抗的反馈环。我们发现了一个由RAS协会(RA)结构域蛋白RAU介导的正反馈环，该环维持RAS活性，并抵消Sprouty介导的负反馈环。RAU有两个RA结构域，它们一起显示出与GTP(鸟苷5‘-三磷酸)负载(活性)RAS的结合偏好。RAU呈均二聚状态，并存在于大分子量络合物中。果蝇中RAU的缺失降低了视网膜包裹神经胶质细胞的分化，并诱导了与RAS信号变化相似的粗糙眼部表型。此外，在弱的但不是结构性的FGFR激活的情况下，Coup转录因子Seven-up抑制了芽的表达，而增加了RAU的表达。总之，我们的发现揭示了另一种调控机制，它控制了果蝇眼睛中发育中的神经网络中RTK信号的强度。
During development, differentiation is often initiated by the activation of different receptor tyrosine kinases (RTKs), which results in the tightly regulated activation of cytoplasmic signaling cascades. In the differentiation of neurons and glia in the developing Drosophila eye, we found that the proper intensity of RTK signaling downstream of fibroblast growth factor receptor (FGFR) or epidermal growth factor receptor required two mutually antagonistic feedback loops. We identified a positive feedback loop mediated by the Ras association (RA) domain-containing protein Rau that sustained Ras activity and counteracted the negative feedback loop mediated by Sprouty. Rau has two RA domains that together showed a binding preference for GTP (guanosine 5 '-triphosphate)-loaded (active) Ras. Rau homodimerized and was found in large-molecular weight complexes. Deletion of rau in flies decreased the differentiation of retinal wrapping glia and induced a rough eye phenotype, similar to that seen in alterations of Ras signaling. Further, the expression of sprouty was repressed and that of rau was increased by the COUP transcription factor Seven-up in the presence of weak, but not constitutive, activation of FGFR. Together, our findings reveal another regulatory mechanism that controls the intensity of RTK signaling in the developing neural network in the Drosophila eye.