GEI-8, a homologue of vertebrate nuclear receptor corepressor NCoR/SMRT, regulates gonad development and neuronal functions in Caenorhabditis elegans.
GEI-8, a homologue of vertebrate nuclear receptor corepressor NCoR/SMRT, regulates gonad development and neuronal functions in Caenorhabditis elegans.
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DOI：
10.1371/journal.pone.0058462
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Kostrouchová M
中科院分区：
文献类型：
--
作者：
Mikoláš P;Kollárová J;Sebková K;Saudek V;Yilma P;Kostrouchová M;Krause MW;Kostrouch Z;Kostrouchová M
NCoR和SMRT是两种旁系同源的脊椎动物蛋白质，其作为非配体核受体的辅阻遏物起作用。虽然C.线虫具有大量的核受体，辅阻遏物NCoR和SMRT的直向同源物在果蝇或C.优雅在这里，我们确定GEI-8作为最接近的同源物的NCoR和SMRT在C。Elegans的研究表明，GEI-8在包括神经元、肌肉和肠细胞在内的多种组织的整个发育过程中表达为至少两种同种型。我们证明，一个纯合性缺失的gei-8编码区，这是预测编码一个截短的蛋白质缺乏预测的NR结构域，导致严重的突变表型与发育缺陷，缓慢的运动和生长，性腺发育受阻和胆碱能神经传递的缺陷。通过微阵列进行的全基因组表达分析鉴定了与观察到的突变体表型和GEI-8在调节转录中的作用一致的去调节基因组。有趣的是，上调的转录物包括预测的线粒体硫化物：奎宁还原酶由Y9C9A.16编码。该基因座还含有皮尔纳类的非编码21-U RNA。抑制21-U RNA编码区的表达会导致纯合gei-8突变体中的不规则性腺发生，但在其他野生型背景中则不会，这表明GEI-8可能与21-U RNA一起调节性腺发生。我们的研究结果证实，GEI-8是直向同源的脊椎动物NCoR/SMRT辅阻遏物，并证明了重要的作用，这种假定的转录辅阻遏物的发展和神经元功能。
NCoR and SMRT are two paralogous vertebrate proteins that function as corepressors with unliganded nuclear receptors. Although C. elegans has a large number of nuclear receptors, orthologues of the corepressors NCoR and SMRT have not unambiguously been identified in Drosophila or C. elegans. Here, we identify GEI-8 as the closest homologue of NCoR and SMRT in C. elegans and demonstrate that GEI-8 is expressed as at least two isoforms throughout development in multiple tissues, including neurons, muscle and intestinal cells. We demonstrate that a homozygous deletion within the gei-8 coding region, which is predicted to encode a truncated protein lacking the predicted NR domain, results in severe mutant phenotypes with developmental defects, slow movement and growth, arrested gonadogenesis and defects in cholinergic neurotransmission. Whole genome expression analysis by microarrays identified sets of de-regulated genes consistent with both the observed mutant phenotypes and a role of GEI-8 in regulating transcription. Interestingly, the upregulated transcripts included a predicted mitochondrial sulfide:quinine reductase encoded by Y9C9A.16. This locus also contains non-coding, 21-U RNAs of the piRNA class. Inhibition of the expression of the region coding for 21-U RNAs leads to irregular gonadogenesis in the homozygous gei-8 mutants, but not in an otherwise wild-type background, suggesting that GEI-8 may function in concert with the 21-U RNAs to regulate gonadogenesis. Our results confirm that GEI-8 is the orthologue of the vertebrate NCoR/SMRT corepressors and demonstrate important roles for this putative transcriptional corepressor in development and neuronal function.
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