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首页> 外文期刊>PLoS Genetics >Loss of the Transcriptional Repressor PAG-3/Gfi-1 Results in Enhanced Neurosecretion that is Dependent on the Dense-Core Vesicle Membrane Protein IDA-1/IA-2
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Loss of the Transcriptional Repressor PAG-3/Gfi-1 Results in Enhanced Neurosecretion that is Dependent on the Dense-Core Vesicle Membrane Protein IDA-1/IA-2

机译：转录阻遏物PAG-3 / Gfi-1的丧失导致神经分泌增强，而神经分泌依赖于密实核心囊泡膜蛋白IDA-1 / IA-2。

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It is generally accepted that neuroendocrine cells regulate dense core vesicle (DCV) biogenesis and cargo packaging in response to secretory demands, although the molecular mechanisms of this process are poorly understood. One factor that has previously been implicated in DCV regulation is IA-2, a catalytically inactive protein phosphatase present in DCV membranes. Our ability to directly visualize a functional, GFP-tagged version of an IA-2 homolog in live Caenorhabditis elegans animals has allowed us to capitalize on the genetics of the system to screen for mutations that disrupt DCV regulation. We found that loss of activity in the transcription factor PAG-3/Gfi-1, which functions as a repressor in many systems, results in a dramatic up-regulation of IDA-1/IA-2 and other DCV proteins. The up-regulation of DCV components was accompanied by an increase in presynaptic DCV numbers and resulted in phenotypes consistent with increased neuroendocrine secretion. Double mutant combinations revealed that these PAG-3 mutant phenotypes were dependent on wild type IDA-1 function. Our results support a model in which IDA-1/IA-2 is a critical element in DCV regulation and reveal a novel genetic link to PAG-3-mediated transcriptional regulation. To our knowledge, this is the first mutation identified that results in increased neurosecretion, a phenotype that has clinical implications for DCV-mediated secretory disorders.
机译：尽管人们对这种过程的分子机理了解甚少，但人们普遍认为神经内分泌细胞可调节分泌的需求来调节致密核心囊泡（DCV）的生物发生和货物包装。以前与DCV调节有关的一个因素是IA-2，它是存在于DCV膜中的一种无催化活性的蛋白磷酸酶。我们能够在活的秀丽隐杆线虫动物中直接可视化IA-2同源物的功能性，带GFP标签的版本，这使我们能够利用系统的遗传学来筛选破坏DCV调控的突变。我们发现转录因子PAG-3 / Gfi-1（在许多系统中起阻遏物的作用）中活性的丧失导致IDA-1 / IA-2和其他DCV蛋白的急剧上调。 DCV成分的上调伴随着突触前DCV数量的增加，并导致与神经内分泌分泌增加相一致的表型。双重突变体组合显示这些PAG-3突变体表型依赖于野生型IDA-1功能。我们的结果支持一个模型，其中IDA-1 / IA-2是DCV调控的关键要素，并揭示了与PAG-3介导的转录调控的新型遗传联系。据我们所知，这是第一个导致神经分泌增加的突变，该表型对DCV介导的分泌性疾病具有临床意义。

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