Hyperactive neuroendocrine secretion causes size, feeding, and metabolic defects of C. elegans Bardet-Biedl syndrome mutants.
Hyperactive neuroendocrine secretion causes size, feeding, and metabolic defects of C. elegans Bardet-Biedl syndrome mutants.
复制标题
过度活跃的神经内分泌分泌会导致秀丽隐杆线虫Bardet-Biedl综合征突变体的大小，进食和代谢缺陷。
DOI：
10.1371/journal.pbio.1001219
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发表时间：
2011-12
期刊：
影响因子：
9.8
通讯作者：
Ashrafi K
中科院分区：
文献类型：
--
作者：
Lee BH;Liu J;Wong D;Srinivasan S;Ashrafi K
Bardet-Biedl综合征，BBS，是一种罕见的常染色体隐性遗传疾病，临床表现包括多指（趾）畸形、视网膜病变、摄食过多、肥胖、身材矮小、认知障碍和发育迟缓。BBS蛋白在多种生物体中的破坏损害纤毛的形成和功能，并且BBS的多器官缺陷已被归因于多种纤毛相关信号通路的缺陷。In C.在线虫中，BBS基因仅在这些动物的60个纤毛感觉神经元中表达，并且BBS突变体表现出感觉缺陷以及体型、进食和代谢异常。在这里，我们表明，与许多其他纤毛缺陷突变体，C。秀丽线虫BBS突变体表现出与胰岛素、神经肽和生物胺信号传导途径的活性增强相关的致密核心囊泡和生物体范围表型的释放增加。我们发现bbs突变体的体型改变、摄食和代谢异常可以通过消除致密核心囊泡的分泌增强而纠正到野生型水平，而不伴随纤毛缺陷的纠正。这些发现扩大了BBS蛋白的作用，致密核心囊泡胞吐的调节，并建议，Bardet-Biedl综合征的一些功能可能是由过度的神经内分泌引起的。Bardet-Biedl综合征（BBS）是一种罕见的人类遗传性疾病，由多个基因突变引起。BBS表型非常复杂;其主要特征是早发性肥胖、进行性失明、手脚多指和肾脏问题。BBS患者还可能患有发育迟缓、学习障碍、糖尿病和嗅觉丧失。这种复杂性表明BBS蛋白在多种组织中发挥作用，导致许多器官的缺陷。当BBS基因被鉴定出来，并且发现它们的蛋白质产物在纤毛（一种在许多细胞类型中发现的感觉结构）中起作用时，BBS的不同特征出现了一个统一的主题。从那时起，BBS的各种表现被归因于相应组织中纤毛功能的丧失。这一观点也得到了以下发现的支持，即正常纤毛形成和功能所需的几个基因的突变重现了BBS患者中观察到的一些特征。在这里，我们进一步研究了在携带BBS基因突变（BBS突变体）的秀丽隐杆线虫菌株中发现的缺陷。我们发现，它们不仅显示与纤毛功能丧失相关的感觉缺陷，而且它们还表现出增加释放的多肽和生物胺激素，这些激素包含在纤毛感觉神经元的致密核心囊泡中。重要的是，在不纠正bbs突变体纤毛缺陷的情况下，限制这种过度的激素释放足以使这些突变体恢复正常的体型、进食和代谢。此外，我们表明，虽然非bbs纤毛突变可以模仿一些表型的bbs突变体，这些影响可以归因于不同的空间和分子机制。结果表明，C.秀丽线虫BBS突变体表现出纤毛和内分泌缺陷的特征，并提示人类BBS的一些临床表现可能是由过度的内分泌活性引起的，而与纤毛功能的丧失无关。
Bardet-Biedl syndrome, BBS, is a rare autosomal recessive disorder with clinical presentations including polydactyly, retinopathy, hyperphagia, obesity, short stature, cognitive impairment, and developmental delays. Disruptions of BBS proteins in a variety of organisms impair cilia formation and function and the multi-organ defects of BBS have been attributed to deficiencies in various cilia-associated signaling pathways. In C. elegans, bbs genes are expressed exclusively in the sixty ciliated sensory neurons of these animals and bbs mutants exhibit sensory defects as well as body size, feeding, and metabolic abnormalities. Here we show that in contrast to many other cilia-defective mutants, C. elegans bbs mutants exhibit increased release of dense-core vesicles and organism-wide phenotypes associated with enhanced activities of insulin, neuropeptide, and biogenic amine signaling pathways. We show that the altered body size, feeding, and metabolic abnormalities of bbs mutants can be corrected to wild-type levels by abrogating the enhanced secretion of dense-core vesicles without concomitant correction of ciliary defects. These findings expand the role of BBS proteins to the regulation of dense-core-vesicle exocytosis and suggest that some features of Bardet-Biedl Syndrome may be caused by excessive neuroendocrine secretion. Bardet-Biedl syndrome, BBS, is a rare human genetic disease caused by mutations in many genes. The BBS phenotype is very complex; it is principally characterized by early-onset obesity, progressive blindness, extra digits on the hands and feet, and renal problems. BBS patients may also suffer from developmental delay, learning disabilities, diabetes, and loss of the sense of smell. This complexity suggests that BBS proteins function in a variety of tissues, causing defects in many organs. A unifying theme for the diverse features of BBS emerged when BBS genes were identified and their protein products were found to function in the cilium, a sensory structure found in many cell types. Since then, the various manifestations of BBS have been attributed to the loss of ciliary function in the corresponding tissues. This notion was also supported by the finding that mutations in several genes required for proper cilia formation and function reproduce some of the features seen in BBS patients. Here, we have further investigated the defects found in Caenorhabditis elegans strains carrying mutations in BBS genes (bbs mutants). We find that not only do they display sensory deficits associated with loss of ciliary function, but they also exhibit increased release of multiple peptide and biogenic amine hormones contained in dense-core vesicles of ciliated sensory neurons. Importantly, limiting this excessive hormonal release without correcting the ciliary defects of bbs mutants was sufficient to restore normal body size, feeding, and metabolism to these mutants. Moreover, we show that although non-bbs ciliary mutations can mimic some of the phenotypes of bbs mutants, these effects can be attributed to distinct spatial and molecular mechanisms. Our findings indicate that C. elegans bbs mutants exhibit features of both ciliary and endocrine defects and suggest that some of the clinical manifestations of human BBS may result from excessive endocrine activity, independently of the loss of ciliary function.
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影响因子：
4.5
作者：
Lee, Brian H.;Ashrafi, Kaveh
通讯作者：
Ashrafi, Kaveh
影响因子：
29
作者：
Greer, Elisabeth R.;Perez, Carissa L.;Van Gilst, Marc R.;Lee, Brian H.;Ashrafi, Kaveh
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分析突触蛋白鉴定了胰岛素分泌和寿命的调节剂。
影响因子：
4.5
作者：
Ch'ng, QueeLim;Sieburth, Derek;Kaplan, Joshua M.
通讯作者：
Kaplan, Joshua M.
影响因子：
64.5
作者：
Kao, Gautam;Nordenson, Cecilia;Naredi, Peter
通讯作者：
Naredi, Peter
DOI：
10.1002/ajmg.c.30231
发表时间：
2009-11-15
影响因子：
3.1
作者：
Baker, Kate;Beales, Philip L.
通讯作者：
Beales, Philip L.