Developmental Function of the PHR Protein RPM-1 Is Required for Learning in Caenorhabditis elegans.
Developmental Function of the PHR Protein RPM-1 Is Required for Learning in Caenorhabditis elegans.
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DOI：
10.1534/g3.115.021410
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发表时间：
2015-10-13
期刊：
影响因子：
--
通讯作者：
Grill B
中科院分区：
文献类型：
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作者：
Giles AC;Opperman KJ;Rankin CH;Grill B
PAM/Highwire/RPM-1 (PHR) 蛋白是信号传导中枢，充当神经发育的重要调节因子。秀丽隐杆线虫 rpm-1 和果蝇 Highwire 的功能丧失会导致轴突终止失败、轴突定位不当和突触形成异常。尽管在神经系统中广泛表达，并且突触形成和轴突发育存在相对显着的缺陷，但在缺乏 PHR 蛋白功能的动物中发现了非常轻微的行为异常。因此，我们假设只有在需要诱发、延长回路功能或发生行为可塑性的情况下才能检测到行为中的大缺陷。使用线虫的定量方法，我们发现rpm-1功能丧失突变体在探索性运动方面具有相对轻微的异常，但在对严厉触摸的诱发反应和与敲击习惯相关的学习方面存在较大缺陷。我们进一步探讨了 rpm-1 突变体严重习惯缺陷的本质。为了解决 rpm-1 突变体中习惯化回路的哪一部分受损，我们对不同神经元的启动子进行了救援分析。我们的研究结果表明，机械感觉神经元中的 RPM-1 功能会影响习惯化。成年动物中 RPM-1 的转基因表达未能挽救习惯性缺陷，这与导致习惯性受损的 rpm-1 突变体的发育缺陷一致。遗传分析表明，在 rpm-1 通路中发挥作用的其他神经元发育调节因子（包括 glo-4、fsn-1 和 dlk-1）也影响习惯化。总体而言，我们的研究结果表明，rpm-1 突变体的发育缺陷最明显地表现在需要长期或可塑性回路功能的行为中，例如学习。
The PAM/Highwire/RPM-1 (PHR) proteins are signaling hubs that function as important regulators of neural development. Loss of function in Caenorhabditis elegans rpm-1 and Drosophila Highwire results in failed axon termination, inappropriate axon targeting, and abnormal synapse formation. Despite broad expression in the nervous system and relatively dramatic defects in synapse formation and axon development, very mild abnormalities in behavior have been found in animals lacking PHR protein function. Therefore, we hypothesized that large defects in behavior might only be detected in scenarios in which evoked, prolonged circuit function is required, or in which behavioral plasticity occurs. Using quantitative approaches in C. elegans, we found that rpm-1 loss-of-function mutants have relatively mild abnormalities in exploratory locomotion, but have large defects in evoked responses to harsh touch and learning associated with tap habituation. We explored the nature of the severe habituation defects in rpm-1 mutants further. To address what part of the habituation circuit was impaired in rpm-1 mutants, we performed rescue analysis with promoters for different neurons. Our findings indicate that RPM-1 function in the mechanosensory neurons affects habituation. Transgenic expression of RPM-1 in adult animals failed to rescue habituation defects, consistent with developmental defects in rpm-1 mutants resulting in impaired habituation. Genetic analysis showed that other regulators of neuronal development that function in the rpm-1 pathway (including glo-4, fsn-1, and dlk-1) also affected habituation. Overall, our findings suggest that developmental defects in rpm-1 mutants manifest most prominently in behaviors that require protracted or plastic circuit function, such as learning.