Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning
Genetic interaction between Bardet-Biedl syndrome genes and implications for limb patterning
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DOI：
10.1093/hmg/ddn093
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发表时间：
2008-07-01
影响因子：
3.5
通讯作者：
Slusarski, Diane C.
中科院分区：
文献类型：
--
作者：
Tayeh, Marwan K.;Yen, Hsan-Jan;Slusarski, Diane C.
Bardet-Biedl 综合征 (BBS) 是一种多效性遗传异质性疾病，其特征为肥胖、视网膜病变、多指、认知障碍、肾脏和心脏异常以及高血压和糖尿病。已知多个基因可独立引起 BBS。这些基因似乎并不编码相同功能类别的蛋白质；然而，每种突变都会导致相似的表型。斑马鱼不同 BBS 基因的基因敲除显示出惊人的重叠表型，包括黑素体运输缺陷和纤毛库普弗囊泡破坏。在这里，我们证明 bbs1 和 bbs3 的单独敲低会产生与之前报道的其他 BBS 基因相同的原型表型。我们利用斑马鱼系统来全面确定 BBS 基因的同时成对敲低是否揭示了 BBS 基因之间的遗传相互作用。使用这种方法，我们证明了 BBS 基因子集之间的八种遗传相互作用。不同组合之间的协同关系不是由于功能冗余，而是表明多亚基 BBS 复合体内的特定相互作用。此外，我们利用斑马鱼模型系统来研究肢体发育。人类多指症是 BBS 的一个主要特征，在 BBS 小鼠模型中并未重现。我们评估了斑马鱼的鳍芽图案，并观察到 Sonic Hedgehog (shh) 表达的改变以及鳍骨骼元素的后续变化。 SHH 鳍芽表型也用于确认 BBS 基因之间的特定遗传相互作用。这项研究揭示了肢芽模式中 BBS 功能的体内需求。我们的结果为 BBS 的机制和生物学意义提供了重要的新见解。
Bardet-Biedl syndrome (BBS) is a pleiotropic, genetically heterogeneous disorder characterized by obesity, retinopathy, polydactyly, cognitive impairment, renal and cardiac anomalies, as well as hypertension and diabetes. Multiple genes are known to independently cause BBS. These genes do not appear to code for the same functional category of proteins; yet, mutation of each results in a similar phenotype. Gene knockdown of different BBS genes in zebrafish shows strikingly overlapping phenotypes including defective melanosome transport and disruption of the ciliated Kupffer's vesicle. Here, we demonstrate that individual knockdown of bbs1 and bbs3 results in the same prototypical phenotypes as reported previously for other BBS genes. We utilize the zebrafish system to comprehensively determine whether simultaneous pair-wise knockdown of BBS genes reveals genetic interactions between BBS genes. Using this approach, we demonstrate eight genetic interactions between a subset of BBS genes. The synergistic relationships between distinct combinations are not due to functional redundancy but indicate specific interactions within a multi-subunit BBS complex. In addition, we utilize the zebrafish model system to investigate limb development. Human polydactyly is a cardinal feature of BBS not reproduced in BBS-mouse models. We evaluated zebrafish fin bud patterning and observed altered Sonic hedgehog (shh) expression and subsequent changes to fin skeletal elements. The SHH fin bud phenotype was also used to confirm specific genetic interactions between BBS genes. This study reveals an in vivo requirement for BBS function in limb bud patterning. Our results provide important new insights into the mechanism and biological significance of BBS.