The Wnt Frizzled Receptor MOM-5 Regulates the UNC-5 Netrin Receptor through Small GTPase-Dependent Signaling to Determine the Polarity of Migrating Cells.
The Wnt Frizzled Receptor MOM-5 Regulates the UNC-5 Netrin Receptor through Small GTPase-Dependent Signaling to Determine the Polarity of Migrating Cells.
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DOI：
10.1371/journal.pgen.1005446
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发表时间：
2015-08
期刊：
影响因子：
4.5
通讯作者：
Culotti JG
中科院分区：
文献类型：
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作者：
Levy-Strumpf N;Krizus M;Zheng H;Brown L;Culotti JG
WNT和Netrin信号调节多种基本功能。利用遗传学方法结合时间基因表达分析，我们发现Wnt受体MoM-5/Frizzled和UNC-6/Netrin受体UNC-5之间存在调控联系。这两种受体在引导细胞和轴突迁移中发挥关键作用，包括线虫远端顶端细胞(DTC)的迁移。DCs在胚胎后的迁移经历了三个连续的阶段：第一阶段沿A/P轴，第二阶段沿D/V轴，第三阶段沿A/P轴。MoM-5/Frizzleed功能的丧失导致迁移的DCs第三相A/P极性反转。我们表明，UNC-5的过度表达会导致类似的DTC A/P极性逆转，而UNC-5的缺失显著抑制了MOM-5/FrizzLED突变引起的A/P极性逆转。这意味着MOM-5/Frizzled是UNC-5的负调控因子。我们进一步证明，小GTP酶介导MoM-5‘S对UNC-5的调节，从而导致小GTP酶如CED-10/RAC和MIG-2/RhoG功能受损的一个结果是UNC-5功能的增加。这项工作证明了Netrin和Wnt信号通路组件之间存在串扰，并为指导信号机制如何整合以协调定向细胞迁移提供了进一步的见解。细胞暴露在大量的环境线索中，这些线索往往会引发相加的、重叠的甚至是相互冲突的输入。来自多个细胞外线索的信息如何整合到细胞内以产生不同的图案，在很大程度上是未知的。Netrin和Wnt信号通路在多种发育过程中起着关键作用，在正常发育和恶性肿瘤中也发挥着关键作用。这两个信号通路参与建立细胞极性，是它们决定器官形状和调节细胞和轴突迁移能力的关键。在这里，我们揭示了Wnt FrizzledR，MOM-5和Netrin受体UNC-5之间的调节联系。我们提出的证据表明，MoM-5/FrizzledGTP酶信号通过负向调节UNC-5 Netrin受体。这种调节连接使得Netrin和Wnt信号通路能够整合，并促进它们在调节细胞迁移极性方面的协调功能。
Wnt and Netrin signaling regulate diverse essential functions. Using a genetic approach combined with temporal gene expression analysis, we found a regulatory link between the Wnt receptor MOM-5/Frizzled and the UNC-6/Netrin receptor UNC-5. These two receptors play key roles in guiding cell and axon migrations, including the migration of the C. elegans Distal Tip Cells (DTCs). DTCs migrate post-embryonically in three sequential phases: in the first phase along the Antero-Posterior (A/P) axis, in the second, along the Dorso-Ventral (D/V) axis, and in the third, along the A/P axis. Loss of MOM-5/Frizzled function causes third phase A/P polarity reversals of the migrating DTCs. We show that an over-expression of UNC-5 causes similar DTC A/P polarity reversals and that unc-5 deficits markedly suppress the A/P polarity reversals caused by mutations in mom-5/frizzled. This implicates MOM-5/Frizzled as a negative regulator of unc-5. We provide further evidence that small GTPases mediate MOM-5’s regulation of unc-5 such that one outcome of impaired function of small GTPases like CED-10/Rac and MIG-2/RhoG is an increase in unc-5 function. The work presented here demonstrates the existence of cross talk between components of the Netrin and Wnt signaling pathways and provides further insights into the way guidance signaling mechanisms are integrated to orchestrate directed cell migration. Cells are exposed to a multitude of environmental cues that are often eliciting additive, overlapping, or even conflicting inputs. How the information from multiple extracellular cues is integrated within the cell to generate distinct patterning is largely unknown. Netrin and Wnt signaling pathways are critical to multiple developmental processes and play key roles in normal development, as well as in malignancies. The involvement of these two signaling pathways in establishing cellular polarity is key to their ability to determine organ shape and to regulate cell and axon migration. Here, we reveal a regulatory link between the Wnt Frizzled receptor, MOM-5, and the Netrin receptor UNC-5. We present evidence showing that MOM-5/Frizzled signals through small GTPases to negatively regulate the UNC-5 Netrin receptor. This regulatory link enables the integration of Netrin and Wnt signaling pathways and facilitates their orchestrated function in mediating polarity of cell migration.