Heterozygous FOXJ1 Mutations Cause Incomplete Ependymal Cell Differentiation and Communicating Hydrocephalus.

IF 3.6 4区 医学 Q3 CELL BIOLOGY Cellular and Molecular Neurobiology Pub Date : 2023-11-01 Epub Date: 2023-08-24 DOI:10.1007/s10571-023-01398-6
Connie C Hou, Danielle Li, Bethany C Berry, Shaokuan Zheng, Rona S Carroll, Mark D Johnson, Hong Wei Yang
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Abstract

Heterozygous mutations affecting FOXJ1, a transcription factor governing multiciliated cell development, have been associated with obstructive hydrocephalus in humans. However, factors that disrupt multiciliated ependymal cell function often cause communicating hydrocephalus, raising questions about whether FOXJ1 mutations cause hydrocephalus primarily by blocking cerebrospinal fluid (CSF) flow or by different mechanisms. Here, we show that heterozygous FOXJ1 mutations are also associated with communicating hydrocephalus in humans and cause communicating hydrocephalus in mice. Disruption of one Foxj1 allele in mice leads to incomplete ependymal cell differentiation and communicating hydrocephalus. Mature ependymal cell number and motile cilia number are decreased, and 12% of motile cilia display abnormal axonemes. We observed decreased microtubule attachment to basal bodies, random localization and orientation of basal body patches, loss of planar cell polarity, and a disruption of unidirectional CSF flow. Thus, heterozygous FOXJ1 mutations impair ventricular multiciliated cell differentiation, thereby causing communicating hydrocephalus. CSF flow obstruction may develop secondarily in some patients harboring FOXJ1 mutations. Heterozygous FOXJ1 mutations impair motile cilia structure and basal body alignment, thereby disrupting CSF flow dynamics and causing communicating hydrocephalus.

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杂合子FOXJ1突变导致室管膜细胞分化不完全和通讯性脑积水。
影响FOXJ1(一种控制多纤毛细胞发育的转录因子)的杂合突变与人类阻塞性脑积水有关。然而,破坏多根室管膜细胞功能的因素经常导致通讯性脑积水,这就提出了FOXJ1突变是否主要通过阻断脑脊液(CSF)流动或通过其他机制导致脑积水的问题。在这里,我们发现杂合子FOXJ1突变也与人类的通讯性脑积水有关,并引起小鼠的通讯性脑积水。小鼠Foxj1等位基因的破坏可导致室管膜细胞分化不完全和通讯性脑积水。室管膜成熟细胞数量和运动纤毛数量减少,12%的运动纤毛轴突异常。我们观察到微管与基底体的附着减少,基底体斑块的随机定位和定向,平面细胞极性的丧失,以及单向CSF流动的中断。因此,杂合的FOXJ1突变损害了心室多纤毛细胞的分化,从而导致通讯性脑积水。一些携带FOXJ1突变的患者可能继发脑脊液血流阻塞。杂合子FOXJ1突变破坏运动性纤毛结构和基底体排列,从而破坏脑脊液流动动力学,引起通讯性脑积水。
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来源期刊
CiteScore
7.70
自引率
0.00%
发文量
137
审稿时长
4-8 weeks
期刊介绍: Cellular and Molecular Neurobiology publishes original research concerned with the analysis of neuronal and brain function at the cellular and subcellular levels. The journal offers timely, peer-reviewed articles that describe anatomic, genetic, physiologic, pharmacologic, and biochemical approaches to the study of neuronal function and the analysis of elementary mechanisms. Studies are presented on isolated mammalian tissues and intact animals, with investigations aimed at the molecular mechanisms or neuronal responses at the level of single cells. Cellular and Molecular Neurobiology also presents studies of the effects of neurons on other organ systems, such as analysis of the electrical or biochemical response to neurotransmitters or neurohormones on smooth muscle or gland cells.
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