PPM-1, a PP2Cα/β phosphatase, regulates axon termination and synapse formation in Caenorhabditis elegans.
PPM-1, a PP2Cα/β phosphatase, regulates axon termination and synapse formation in Caenorhabditis elegans.
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DOI：
10.1534/genetics.111.134791
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发表时间：
2011-12
期刊：
影响因子：
3.3
通讯作者：
Grill B
中科院分区：
文献类型：
--
作者：
Tulgren ED;Baker ST;Rapp L;Gurney AM;Grill B
PHR (Pam/Highwire/RPM-1) 蛋白是进化上保守的泛素连接酶，可调节秀丽隐杆线虫、果蝇、斑马鱼和小鼠的轴突引导和突触形成。在秀丽隐杆线虫中，RPM-1（突触前形态调节因子-1）在突触形成、轴突引导、轴突终止和突触后 GLR-1 运输中发挥作用。作为 E3 泛素连接酶，RPM-1 负向调节 MAP 激酶通路，包括：dlk-1、mkk-4 和 p38 MAPK、pmk-3。在这里，我们提供的证据表明，ppm-1（一种与人 PP2Cα（PPM1A）和 PP2Cβ（PPM1B）同源的丝氨酸/苏氨酸磷酸酶）充当控制 dlk-1 途径的第二个负调节机制。我们表明，ppm-1 通过其磷酸酶活性在与 glo-4 和 fsn-1 平行的遗传途径中发挥作用，调节 GABA 能运动神经元中的突触形成和机械感觉神经元中的轴突终止。我们的转基因分析表明，ppm-1 在 rpm-1 下游发挥作用，对 DLK-1 途径产生负调节，其中 PPM-1 最有可能在 pmk-3 水平发挥作用。我们的研究深入了解了控制神经元中 dlk-1 通路的负调节机制，并证明了 PP2C/PPM 磷酸酶作为神经元发育调节剂的新作用。
The PHR (Pam/Highwire/RPM-1) proteins are evolutionarily conserved ubiquitin ligases that regulate axon guidance and synapse formation in Caenorhabditis elegans, Drosophila, zebrafish, and mice. In C. elegans, RPM-1 (Regulator of Presynaptic Morphology-1) functions in synapse formation, axon guidance, axon termination, and postsynaptic GLR-1 trafficking. Acting as an E3 ubiquitin ligase, RPM-1 negatively regulates a MAP kinase pathway that includes: dlk-1, mkk-4, and the p38 MAPK, pmk-3. Here we provide evidence that ppm-1, a serine/threonine phosphatase homologous to human PP2Cα(PPM1A) and PP2Cβ(PPM1B) acts as a second negative regulatory mechanism to control the dlk-1 pathway. We show that ppm-1 functions through its phosphatase activity in a parallel genetic pathway with glo-4 and fsn-1 to regulate both synapse formation in the GABAergic motorneurons and axon termination in the mechanosensory neurons. Our transgenic analysis shows that ppm-1 acts downstream of rpm-1 to negatively regulate the DLK-1 pathway, with PPM-1 most likely acting at the level of pmk-3. Our study provides insight into the negative regulatory mechanisms that control the dlk-1 pathway in neurons and demonstrates a new role for the PP2C/PPM phosphatases as regulators of neuronal development.