A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus
A novel murine allele of Intraflagellar Transport Protein 172 causes a syndrome including VACTERL-like features with hydrocephalus
复制标题
DOI：
10.1093/hmg/ddr241
复制
发表时间：
2011-10-01
影响因子：
3.5
通讯作者：
Moskowitz, Ivan P.
中科院分区：
文献类型：
--
作者：
Friedland-Little, Joshua M.;Hoffmann, Andrew D.;Moskowitz, Ivan P.
初级纤毛正在成为脊椎动物发育和人类疾病信号通路的重要调节器。我们确定了房室通道1（avc 1），一种导致VEGEL与脑积水相关的小鼠突变，或VEGEL-H。我们发现，avc 1是鞭毛内转运蛋白172（Ift 172），纤毛发生和刺猬（Hh）信号所需的亚型突变。从表型上看，avc 1引起VEGIL-H，但不引起左右（L-R）轴形成异常。Avc 1导致纤毛结构缺陷，包括体内和体外纤毛截短。我们使用Ift 172（avc 1）和Ift 172（wim）（Ift 172无效等位基因）产生的等位基因系列观察到纤毛发生对Ift 172的剂量依赖性需求：纤毛存在于42%的avc 1小鼠胚胎成纤维细胞（MEF）和28%的avc 1/wim MEF上，而野生型MEF>90%。此外，定量纤毛长度分析确定了两个特定的纤毛人口突变MEFS：正常人口与正常IFT和截断人口，正常长度的50%，中断IFT。来自野生型胚胎的细胞主要具有全长纤毛，具有Hh信号异常但不具有L-R异常的avc 1胚胎具有在全长和截短之间均等划分的纤毛，并且具有Hh信号和L-R异常的avc 1/wim胚胎主要被截短。截短的Ift 172突变体纤毛显示远端纤毛轴丝的缺陷，包括破坏的IFFT 88定位和Hh依赖的Gli 2定位。我们提出了一个模型，其中Ift 172的突变导致特定类别的异常纤毛，导致破坏Hh信号传导，同时维持L-R轴的决定，并导致VEGIL-H表型。
The primary cilium is emerging as a crucial regulator of signaling pathways central to vertebrate development and human disease. We identified atrioventricular canal 1 (avc1), a mouse mutation that caused VACTERL association with hydrocephalus, or VACTERL-H. We showed that avc1 is a hypomorphic mutation of intraflagellar transport protein 172 (Ift172), required for ciliogenesis and Hedgehog (Hh) signaling. Phenotypically, avc1 caused VACTERL-H but not abnormalities in left-right (L-R) axis formation. Avc1 resulted in structural cilia defects, including truncated cilia in vivo and in vitro. We observed a dose-dependent requirement for Ift172 in ciliogenesis using an allelic series generated with Ift172(avc1) and Ift172(wim), an Ift172 null allele: cilia were present on 42% of avc1 mouse embryonic fibroblast (MEF) and 28% of avc1/wim MEFs, in contrast to >90% of wild-type MEFs. Furthermore, quantitative cilium length analysis identified two specific cilium populations in mutant MEFS: a normal population with normal IFT and a truncated population, 50% of normal length, with disrupted IFT. Cells from wild-type embryos had predominantly full-length cilia, avc1 embryos, with Hh signaling abnormalities but not L-R abnormalities, had cilia equally divided between full-length and truncated, and avc1/wim embryos, with both Hh signaling and L-R abnormalities, were primarily truncated. Truncated Ift172 mutant cilia showed defects of the distal ciliary axoneme, including disrupted IFT88 localization and Hh-dependent Gli2 localization. We propose a model in which mutation of Ift172 results in a specific class of abnormal cilia, causing disrupted Hh signaling while maintaining L-R axis determination, and resulting in the VACTERL-H phenotype.