Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus
Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus
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DOI：
10.1242/dev.02153
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发表时间：
2005-12-01
期刊：
影响因子：
4.6
通讯作者：
Yoder, BK
中科院分区：
文献类型：
--
作者：
Banizs, B;Pike, MM;Yoder, BK
纤毛是复杂的细胞器，参与感觉知觉和流体或细胞运动。它们是通过一种高度保守的称为鞭毛内运输（IFT）的过程构建的。IFT基因的突变，如Tg737，会导致严重的发育缺陷和疾病。在Tg737（orpk）突变体的情况下，这些病理学改变包括囊性肾病、胆管和胰管异常、骨骼图案缺陷和脑积水。在这里，我们探索纤毛功能障碍和脑积水的发展之间的联系，通过使用Tg737（orpk）突变体。我们的分析表明，纤毛细胞的Tg737（orpk）突变小鼠的脑室严重畸形。在室管膜细胞上，这些缺陷导致搏动紊乱和脑脊液（CSF）运动受损。然而，纤毛搏动和CSF流动的损失不是起始因素，因为病理学在这些细胞上的运动纤毛发育之前就存在，并且CSF流动在疾病的早期阶段不受损害。相反，我们的研究结果表明，纤毛的损失导致脉络丛上皮的功能改变，如通过升高的细胞内cAMP水平和增加的CSF中的氯离子浓度所证明的。这些数据表明，纤毛功能是必要的调节离子转运和CSF的生产，以及CSF流经脑室。
Cilia are complex organelles involved in sensory perception and fluid or cell movement. They are constructed through a highly conserved process called intraflagellar transport (IFT). Mutations in IFT genes, such as Tg737, result in severe developmental defects and disease. In the case of the Tg737(orpk) mutants, these pathological alterations include cystic kidney disease, biliary and pancreatic duct abnormalities, skeletal patterning defects, and hydrocephalus. Here, we explore the connection between cilia dysfunction and the development of hydrocephalus by using the Tg737(orpk) mutants. Our analysis indicates that cilia on cells of the brain ventricles of Tg737(orpk) mutant mice are severely malformed. On the ependymal cells, these defects lead to disorganized beating and impaired cerebrospinal fluid (CSF) movement. However, the loss of the cilia beat and CSF flow is not the initiating factor, as the pathology is present prior to the development of motile cilia on these cells and CSF flow is not impaired at early stages of the disease. Rather, our results suggest that loss of cilia leads to altered function of the choroid plexus epithelum, as evidenced by elevated intracellular cAMP levels and increased chloride concentration in the CSF These data suggest that cilia function is necessary for regulating ion transport and CSF production, as well as for CSF flow through the ventricles.