Characterization of Caenorhabditis elegans homologs of the Down syndrome candidate gene DYRK1A.
Characterization of Caenorhabditis elegans homologs of the Down syndrome candidate gene DYRK1A.
复制标题
唐氏综合症候选基因 DYRK1A 的秀丽隐杆线虫同源物的表征。
DOI：
10.1093/genetics/163.2.571
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发表时间：
2003
期刊：
影响因子：
3.3
通讯作者：
Hobert,Oliver
中科院分区：
文献类型：
--
作者：
Raich,WilliamB;Moorman,Celine;Lacefield,ClayO;Lehrer,Jonah;Bartsch,Dusan;Plasterk,RonaldHA;Kandel,EricR;Hobert,Oliver
21三体/唐氏综合征的病理包括认知和记忆缺陷。双特异性蛋白激酶DYRK1AK(DYRK1AK)的高表达似乎在唐氏综合征的神经病理中起着重要作用。为了阐明DYRK1a及其相关基因在细胞中的作用，我们在秀丽线虫基因组序列中发现了3个DYRK/mini Brain样基因：termedmbk-1、MBK-2和hpk-1。我们发现这些基因广泛表达并定位于不同的亚细胞区段。我们分离了这三个基因中的缺失等位基因，结果表明，与DYRK1A关系最密切的基因MBK-1的缺失不会导致明显的缺陷，而另一个基因MBK-2对生存是必不可少的。DYRK1A在唐氏综合征中的过度表达使我们研究了其C的过度表达的影响。我们发现，含有额外bk-1基因拷贝的动物对挥发性趋化物质的趋化行为存在缺陷，并且这些缺陷的程度与mbk-1基因的剂量有关。利用组织特异性和可诱导的启动子，我们证明了额外的MBK-1拷贝可以自主地损害成熟的、完全分化的神经元中的嗅觉细胞，并且这种损害是可逆的。我们的结果表明，在21三体中增加人类DYRK1A的基因剂量可能会破坏完全分化的神经元的功能，并且这种破坏是可逆的。
The pathology of trisomy 21/Down syndrome includes cognitive and memory deficits. Increased expression of the dual-specificity protein kinase DYRK1A kinase (DYRK1A) appears to play a significant role in the neuropathology of Down syndrome. To shed light on the cellular role of DYRK1A and related genes we identified threeDYRK/minibrain-like genes in the genome sequence ofCaenorhabditis elegans, termedmbk-1, mbk-2, andhpk-1.We found these genes to be widely expressed and to localize to distinct subcellular compartments. We isolated deletion alleles in all three genes and show that loss ofmbk-1, the gene most closely related to DYRK1A, causes no obvious defects, while another gene,mbk-2, is essential for viability. The overexpression of DYRK1A in Down syndrome led us to examine the effects of overexpression of itsC. elegansorthologmbk-1.We found that animals containing additional copies of thembk-1gene display behavioral defects in chemotaxis toward volatile chemoattractants and that the extent of these defects correlates withmbk-1gene dosage. Using tissue-specific and inducible promoters, we show that additional copies ofmbk-1can impair olfaction cell-autonomously in mature, fully differentiated neurons and that this impairment is reversible. Our results suggest that increased gene dosage of human DYRK1A in trisomy 21 may disrupt the function of fully differentiated neurons and that this disruption is reversible.