Duy Phan Q, Greenberg Ana B W, Butler William E, Kahle Kristopher T
Department of Neuroscience, Yale University School of Medicine, New Haven, CT, USA; Medical Scientist Training Program, Yale University School of Medicine, New Haven, CT, USA; Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA; Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
Department of Neurosurgery, Massachusetts General Hospital, Boston, MA, USA.
Neurobiol Dis. 2022 Dec;175:105913. doi: 10.1016/j.nbd.2022.105913. Epub 2022 Oct 29.
Dysfunction of motile cilia in ependymal cells has been proposed to be a pathogenic cause of cerebrospinal fluid (CSF) overaccumulation leading to ventricular expansion in hydrocephalus, primarily based on observations of enlarged ventricles in mouse models of primary ciliary dyskinesia. Here, we review human and animal evidence that warrants a rethinking of the cilia hypothesis in hydrocephalus. First, we discuss neuroembryology and physiology data that do not support a role for ependymal cilia as the primary propeller of CSF movement across the ventricles in the human brain, particularly during in utero development prior to the functional maturation of ependymal cilia. Second, we highlight that in contrast to mouse models, motile ciliopathies infrequently cause hydrocephalus in humans. Instead, gene mutations affecting motile cilia function impact not only ependymal cilia but also motile cilia found in other organ systems outside of the brain, causing a clinical syndrome of recurrent respiratory infections and situs inversus, symptoms that do not typically accompany most cases of human hydrocephalus. Finally, we postulate that certain cases of hydrocephalus associated with ciliary gene mutations may arise not necessarily just from loss of cilia-generated CSF flow but also from altered neurodevelopment, given the potential functions of ciliary genes in signaling and neural stem cell fate beyond generating fluid flow. Further investigations are needed to clarify the link between motile cilia, CSF physiology, and brain development, the understanding of which has implications for the care of patients with hydrocephalus and other related neurodevelopmental disorders.
室管膜细胞中运动性纤毛功能障碍被认为是脑积水时脑脊液（CSF）过度积聚导致脑室扩张的致病原因，这主要基于对原发性纤毛运动障碍小鼠模型中脑室扩大的观察。在此，我们回顾人类和动物证据，这些证据表明有必要重新思考脑积水的纤毛假说。首先，我们讨论神经胚胎学和生理学数据，这些数据不支持室管膜纤毛作为人类大脑中脑脊液跨脑室流动的主要推动者，特别是在室管膜纤毛功能成熟之前的子宫内发育期间。其次，我们强调，与小鼠模型不同，运动性纤毛病在人类中很少导致脑积水。相反，影响运动性纤毛功能的基因突变不仅会影响室管膜纤毛，还会影响大脑以外其他器官系统中的运动性纤毛，导致反复呼吸道感染和内脏反位的临床综合征，而这些症状在大多数人类脑积水病例中并不常见。最后，我们推测，某些与纤毛基因突变相关的脑积水病例不一定仅仅源于纤毛产生的脑脊液流动丧失，还可能源于神经发育改变，因为纤毛基因除了产生液体流动外，在信号传导和神经干细胞命运方面具有潜在功能。需要进一步研究来阐明运动性纤毛、脑脊液生理学和大脑发育之间的联系，对这一联系的理解对脑积水和其他相关神经发育障碍患者的护理具有重要意义。
