C. elegans PVF-1 inhibits permissive UNC-40 signalling through CED-10 GTPase to position the male ray 1 sensillum
C. elegans PVF-1 inhibits permissive UNC-40 signalling through CED-10 GTPase to position the male ray 1 sensillum
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DOI：
10.1242/dev.095190
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发表时间：
2013-10-01
期刊：
影响因子：
4.6
通讯作者：
Culotti, Joseph
中科院分区：
文献类型：
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作者：
Dalpe, Gratien;Tarsitano, Marina;Culotti, Joseph
netrin和semaphorin引导线索的分级分布向迁移细胞和生长锥传递指导性极性信息，但在哺乳动物发育和修复中也具有允许（即非极性决定）功能。这些线索的许可功能在分子水平上基本上没有特征。我们以前发现，β-6（netrin）通过β-40（DCC）和β-5受体允许性地发出信号，以阻止C. elegans雄性尾巴。UNC 6/P40信号传导与SMP-1（信号通道蛋白1）/PLX-1（丛蛋白）信号传导并行起作用以防止该缺陷。在这里，我们报告说，pvf-1，它编码的VEGF相关蛋白的缺失等位基因，导致没有射线1缺陷，但增强射线1缺陷的plx-1突变体，并出乎意料地还抑制unc-6（ev 400）-无效突变射线1缺陷。unc-40（+）和ced-10（功能获得性）多拷贝转基因阵列诱导ray 1缺陷或抑制unc-6突变ray 1缺陷的能力模拟了这些突变ray 1诱导和抑制作用，这取决于它们的剂量，这表明pvf-1突变导致干扰信号传导但对ray-6部分敏感的ray-40过度活性。另外的数据表明PVF-1通过四种VEGF受体相关蛋白发挥作用，并且仅抑制CED-10（一种GTP酶），但不抑制CED-2依赖的CED-40活性，即使CED-40通过两种GTP酶发挥作用以定位射线1。pvf-1和受体突变体ray 1缺陷分别被表达小鼠VEGF 164和人VEGF受体的转基因挽救。这些数据报告了第一例VEGF诱导的netrin信号转导抑制和VEGF功能从蠕虫到人类的分子保守。
Graded distributions of netrin and semaphorin guidance cues convey instructive polarity information to migrating cells and growth cones, but also have permissive (i.e. non-polarity determining) functions in mammalian development and repair. The permissive functions of these cues are largely uncharacterised at a molecular level. We found previously that UNC-6 (netrin) signals permissively through UNC-40 (DCC) and UNC-5 receptors to prevent anterior displacement of the ray 1 sensillum in the C. elegans male tail. UNC6/UNC-40 signalling functions in parallel with SMP-1 (semaporin 1)/PLX-1 (plexin) signalling to prevent this defect. Here, we report that a deletion allele of pvf-1, which encodes a VEGF-related protein, causes no ray 1 defects, but enhances ray 1 defects of a plx-1 mutant, and unexpectedly also suppresses unc-6(ev400)-null mutant ray 1 defects. These mutant ray 1 inductive and suppressive effects are mimicked by the ability of unc-40(+) and ced-10(gain-of-function) multi-copy transgene arrays to induce ray 1 defects or suppress unc-6 mutant ray 1 defects, depending on their dosage, suggesting the pvf-1 mutation causes UNC-40 overactivity that interferes with signalling but is partially sensitive to UNC-6. Additional data suggest PVF-1 functions through four VEGF receptorrelated proteins and inhibits only CED-10 (a GTPase), but not MIG-2-dependent UNC-40 activity, even though UNC-40 functions through both GTPases to position ray 1. pvf-1 and receptor mutant ray 1 defects are rescued by transgenes expressing mouse VEGF164 and human VEGF receptors, respectively. These data report the first case of VEGF-induced inhibition of the netrin signalling and a molecular conservation of VEGF function from worms to humans.