Reciprocal regulatory interactions between the Notch and Ras signaling pathways in the Drosophila embryonic mesoderm
Reciprocal regulatory interactions between the Notch and Ras signaling pathways in the Drosophila embryonic mesoderm
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DOI：
10.1006/dbio.2002.0606
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发表时间：
2002-04-15
影响因子：
2.7
通讯作者：
Michelson, AM
中科院分区：
文献类型：
--
作者：
Carmena, A;Buff, E;Michelson, AM
融合的细胞间信号必须被精确整合，才能引起特定的生物反应。在果蝇胚胎中胚层的肌肉和心脏祖细胞的鉴定过程中，由表皮和成纤维细胞生长因子受体激活的RAS/MAPK通路作为诱导性细胞决定信号发挥作用，而Notch介导的侧向抑制则拮抗这一活性。必须实现这些信号之间的关键平衡，以使等价组中的一个细胞能够分离为祖细胞，而其邻居则承担非祖细胞身份。我们已经研究了这些相反的信号是否直接相互作用，我们已经研究了它们如何被响应的细胞整合以确定它们独特的命运。我们的发现表明，RAS和Notch并不是独立发挥作用的；相反，我们发现了这些通路之间的几种串扰模式。RAS诱导Notch、其配体Delta和表皮生长因子受体拮抗剂Argos。我们证明Delta和Argos然后协同作用，非自主地阻止一个正的自动调节反馈环，该环放大了命运诱导的RAS信号。这种反馈环的特征是RAS介导的表皮和成纤维细胞生长因子受体通路的近端成分上调。反过来，Notch在非前体细胞中的激活诱导其自身的表达，并同时抑制Delta和Argos的水平，从而加强了单向抑制反应。这些相互作用结合在一起，产生了信号阈值，这对于从一组最初相等的细胞中正确地确定祖细胞和非祖细胞是必不可少的。(C)2002年埃尔塞维尔科学公司(美国)。
Convergent intercellular signals must be precisely integrated in order to elicit specific biological responses. During specification of muscle and cardiac progenitors from clusters of equivalent cells in the Drosophila embryonic mesoderm, the Ras/MAPK pathway-activated by both epidermal and fibroblast growth factor receptors-functions as an inductive cellular determination signal, while lateral inhibition mediated by Notch antagonizes this activity. A critical balance between these signals must be achieved to enable one cell of an equivalence group to segregate as a progenitor while its neighbors assume a nonprogenitor identity. We have investigated whether these opposing signals directly interact with each other, and we have examined how they are integrated by the responding cells to specify their unique fates. Our findings reveal that Ras and Notch do not function independently; rather, we have uncovered several modes of cross-talk between these pathways. Ras induces Notch, its ligand Delta, and the epidermal growth factor receptor antagonist, Argos. We show that Delta and Argos then synergize to nonautonomously block a positive autoregulatory feedback loop that amplifies a fate-inducing Ras signal. This feedback loop is characterized by Ras-mediated upregulation of proximal components of both the epidermal and fibroblast growth factor receptor pathways. In turn, Notch activation in nonprogenitors induces its own expression and simultaneously suppresses both Delta and Argos levels, thereby reinforcing a unidirectional inhibitory response. These reciprocal interactions combine to generate the signal thresholds that are essential for proper specification of progenitors and nonprogenitors from groups of initially equivalent cells. (C) 2002 Elsevier Science (USA).