Inhibition of ependymal flow during brain development: A novel mechanism for hydrocephalus formation

Motility of unicellular organisms occurred early in evolution with the emergence of cilia and flagella, which propel these organisms through fluid. In vertebrates, motile cilia are required for numerous functions such as clearance of the respiratory sytem and determination of left-right body asymmetry. Ependymal cells lining the brain ventricles also carry motile cilia, but their biological function remained unknown. Here, we show that ependymal cilia generate a laminar flow of cerebrospinal fluid through the cerebral aqueduct, which we term ‘ependymal flow’ in analogy to the ‘nodal flow’, which is generated by nodal cilia. The axonemal dynein heavy chain gene Mdnah5 is specifically expressed in ependymal cells, and is essential for ultrastructural and functional integrity of ependymal cilia. In Mdnah5 mutant mice, lack of ependymal flow causes closure of the aqueduct and subsequent formation of triventricular hydrocephalus during late brain development. The higher incidence of congenital aqueduct closure and hydrocephalus formation in patients with primary ciliary dyskinesia (1: 40) proves the relevance of this novel mechanism in humans.