Determination of EGFR Signaling Output by Opposing Gradients of BMP and JAK/STAT Activity
Determination of EGFR Signaling Output by Opposing Gradients of BMP and JAK/STAT Activity
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DOI：
10.1016/j.cub.2016.07.073
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发表时间：
2016-10-10
期刊：
影响因子：
9.2
通讯作者：
Nilson, Laura A.
中科院分区：
文献类型：
--
作者：
Lomas, Mariana Fregoso;De Vito, Scott;Nilson, Laura A.
数量相对较少的信号通路驱动着广泛的发育决定，但这种信号结果的多样性是如何产生的尚不清楚。在果蝇的毛囊上皮中，局部的表皮生长因子受体(EGFR)激活会根据其所在的位置诱导不同的细胞命运。后部毛囊细胞通过表达T-box转录因子Midline和H15来响应EGFR活性，而前部毛囊细胞通过表达同源结构域转录因子Mirror来响应。我们表明，在这些EGFR信号的替代输出之间的选择受到JAK/STAT和BMP途径活性的反平行梯度的调节，并且Midline/H15和Mirror之间的相互抑制产生了一个双稳态开关，在替代的EGFR信号结果之间切换。JAK/STAT和BMP通路的输入是通过它们对开关两侧的联合和相反的调节来整合的。通过将这种位置信息转换成EGFR信号结果之间的二元决定，这个调控网络最终允许相同的配体-受体对建立组织的前后(AP)和背部-腹侧(DV)轴。
A relatively small number of signaling pathways drive a wide range of developmental decisions, but how this versatility in signaling outcome is generated is not clear. In the Drosophila follicular epithelium, localized epidermal growth factor receptor (EGFR) activation induces distinct cell fates depending on its location. Posterior follicle cells respond to EGFR activity by expressing the T-box transcription factors Midline and H15, while anterior cells respond by expressing the homeodomain transcription factor Mirror. We show that the choice between these alternative outputs of EGFR signaling is regulated by antiparallel gradients of JAK/STAT and BMP pathway activity and that mutual repression between Midline/H15 and Mirror generates a bistable switch that toggles between alternative EGFR signaling outcomes. JAK/STAT and BMP pathway input is integrated through their joint and opposing regulation of both sides of this switch. By converting this positional information into a binary decision between EGFR signaling outcomes, this regulatory network ultimately allows the same ligand-receptor pair to establish both the anterior-posterior (AP) and dorsal-ventral (DV) axes of the tissue.