Department of Anatomy and Cell Biology, Interdisciplinary School of Medicine & Engineering, University of Yamanashi, 1110 Shimo-Kateau, Chuo, Yamanashi 409-3898, Japan.
Traffic. 2010 Feb;11(2):287-301. doi: 10.1111/j.1600-0854.2009.01016.x. Epub 2009 Nov 17.
Functional defects in cilia are associated with various human diseases including congenital hydrocephalus. Previous studies suggested that defects in cilia not only disrupt the flow of cerebrospinal fluid (CSF) generated by motile cilia in ependyma lining the brain ventricles, but also cause increased CSF production at the choroid plexus. However, the molecular mechanisms of CSF overproduction by ciliary dysfunction remain elusive. To dissect the molecular mechanisms, choroid plexus epithelial cells (CPECs) were isolated from porcine brain. These cells expressed clusters of primary cilia on the apical surface. Deciliation of CPECs elevated the intracellular cyclic AMP (cAMP) levels and stimulated basolateral-to-apical fluid transcytosis, without detrimental effects on other morphological and physiological features. The primary cilia possessed neuropeptide FF (NPFF) receptor 2. In deciliated cells, the responsiveness to NPFF was reduced at nanomolar concentrations. Furthermore, CPECs expressed NPFF precursor along with NPFFR2. An NPFFR antagonist, BIBP3226, increased the fluid transcytosis, suggesting the presence of autocrine NPFF signaling in CPECs for a tonic inhibition of fluid transcytosis. These results suggest that the clusters of primary cilia in CPECs act as a sensitive chemosensor to regulate CSF production.
纤毛功能缺陷与多种人类疾病有关，包括先天性脑积水。先前的研究表明，纤毛缺陷不仅会破坏脑室内室管膜运动纤毛产生的脑脊液（CSF）的流动，还会导致脉络丛产生更多的 CSF。然而，纤毛功能障碍导致 CSF 产生过多的分子机制仍不清楚。为了剖析这些分子机制，我们从猪脑中分离出脉络丛上皮细胞（CPECs）。这些细胞在顶表面表达初级纤毛簇。CPEC 的纤毛去化会升高细胞内环磷酸腺苷（cAMP）水平，并刺激基底外侧到顶侧的液体转胞运输，而对其他形态和生理特征没有不利影响。初级纤毛具有神经肽 FF（NPFF）受体 2。在去纤毛细胞中，对 NPFF 的反应性在纳摩尔浓度下降低。此外，CPEC 表达 NPFF 前体和 NPFFR2。NPFFR 拮抗剂 BIBP3226 增加了液体转胞运输，表明 CPECs 中存在自分泌 NPFF 信号，对液体转胞运输进行紧张性抑制。这些结果表明，CPECs 中的初级纤毛簇作为一种敏感的化学感受器，调节 CSF 的产生。
