Abdelhamed Zakia, Vuong Shawn M, Hill Lauren, Shula Crystal, Timms Andrew, Beier David, Campbell Kenneth, Mangano Francesco T, Stottmann Rolf W, Goto June
Division of Pediatric Neurosurgery, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH 45242, USA.
Department of Anatomy and Embryology, Faculty of Medicine (Girls' Section), Al-Azhar University, Cairo 11651, Egypt.
Development. 2018 Jan 9;145(1):dev154500. doi: 10.1242/dev.154500.
Pediatric hydrocephalus is characterized by an abnormal accumulation of cerebrospinal fluid (CSF) and is one of the most common congenital brain abnormalities. However, little is known about the molecular and cellular mechanisms regulating CSF flow in the developing brain. Through whole-genome sequencing analysis, we report that a homozygous splice site mutation in coiled-coil domain containing 39 () is responsible for early postnatal hydrocephalus in the () mouse mutant. is selectively expressed in embryonic choroid plexus and ependymal cells on the medial wall of the forebrain ventricle, and the protein is localized to the axoneme of motile cilia. The ependymal cells develop shorter cilia with disorganized microtubules lacking the axonemal inner arm dynein. Using high-speed video microscopy, we show that an orchestrated ependymal ciliary beating pattern controls unidirectional CSF flow on the ventricular surface, which generates bulk CSF flow in the developing brain. Collectively, our data provide the first evidence for involvement of in hydrocephalus and suggest that the proper development of medial wall ependymal cilia is crucial for normal mouse brain development.
小儿脑积水的特征是脑脊液（CSF）异常积聚，是最常见的先天性脑异常之一。然而，关于发育中的大脑中调节脑脊液流动的分子和细胞机制知之甚少。通过全基因组测序分析，我们报告称，包含卷曲螺旋结构域39（CCDC39）的纯合剪接位点突变是导致Ccdc39基因敲除（Ccdc39−/−）小鼠突变体出生后早期脑积水的原因。Ccdc39在前脑室内侧壁的胚胎脉络丛和室管膜细胞中选择性表达，并且该蛋白定位于运动纤毛的轴丝上。Ccdc39−/−室管膜细胞发育出较短的纤毛，微管排列紊乱，缺乏轴丝内臂动力蛋白。使用高速视频显微镜，我们表明精心编排的室管膜纤毛跳动模式控制着脑室表面的单向脑脊液流动，从而在发育中的大脑中产生大量脑脊液流动。总体而言，我们的数据为Ccdc39参与脑积水提供了首个证据，并表明内侧壁室管膜纤毛的正常发育对正常小鼠脑发育至关重要。
