Primary ciliary dyskinesia in mice lacking the novel ciliary protein Pcdp1
Primary ciliary dyskinesia in mice lacking the novel ciliary protein Pcdp1
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DOI：
10.1128/mcb.00354-07
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发表时间：
2008-02-01
影响因子：
5.3
通讯作者：
Fleming, Mark D.
中科院分区：
文献类型：
--
作者：
Lee, Lance;Campagna, Dean R.;Fleming, Mark D.
原发性纤毛运动障碍（PCD）是由纤毛功能障碍引起的，通常以鼻窦炎、男性不育、脑积水和内脏逆位为特征。nm1054突变纯合子小鼠出现与PCD相关的表型。在某些遗传背景下，纯合子突变体在围产期死于严重的脑积水，而在其他背景下的小鼠具有鼻窦腔中的粘液积聚和雄性不育。突变精子缺乏成熟的鞭毛，而呼吸上皮纤毛存在，但比野生型纤毛跳动的频率慢。转基因拯救表明，nm1054突变体中的PCD是由于编码新的初级纤毛运动障碍蛋白1（Pcdp1）的单个基因的丢失所致。Pcdp1基因在生精细胞和能动纤毛上皮细胞中表达。免疫组织化学显示，Pcdp1蛋白定位于精子鞭毛和纤毛的呼吸上皮细胞和大脑室管膜细胞在小鼠和人类。这项研究表明，Pcdp1在纤毛和鞭毛的生物发生和运动中起着重要的作用，使nm1054突变体研究PCD的分子遗传学和发病机制的一个有用的模型。
Primary ciliary dyskinesia (PCD) results from ciliary dysfunction and is commonly characterized by sinusitis, male infertility, hydrocephalus, and situs inversus. Mice homozygous for the nm1054 mutation develop phenotypes associated with PCD. On certain genetic backgrounds, homozygous mutants die perinatally from severe hydrocephalus, while mice on other backgrounds have an accumulation of mucus in the sinus cavity and male infertility. Mutant sperm lack mature flagella, while respiratory epithelial cilia are present but beat at a slower frequency than wild-type cilia. Transgenic rescue demonstrates that the PCD in nm1054 mutants results from the loss of a single gene encoding the novel primary ciliary dyskinesia protein 1 (Pcdp1). The Pcdp1 gene is expressed in spermatogenic cells and motile ciliated epithelial cells. Immunohistochemistry shows that Pcdp1 protein localizes to sperm flagella and the cilia of respiratory epithelial cells and brain ependymal cells in both mice and humans. This study demonstrates that Pcdp1 plays an important role in ciliary and flagellar biogenesis and motility, making the nm1054 mutant a useful model for studying the molecular genetics and pathogenesis of PCD.