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Human Molecular Genetics Advance Access originally published online on July 21, 2004
Human Molecular Genetics 2004 13(18):2133-2141; doi:10.1093/hmg/ddh219
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Human Molecular Genetics, Vol. 13, No. 18 © Oxford University Press 2004; all rights reserved

Dysfunction of axonemal dynein heavy chain Mdnah5 inhibits ependymal flow and reveals a novel mechanism for hydrocephalus formation

Inés Ibañez-Tallon1, Axel Pagenstecher2, Manfred Fliegauf3, Heike Olbrich3, Andreas Kispert4, Uwe-Peter Ketelsen3, Alison North5, Nathaniel Heintz1 and Heymut Omran3,*

1Laboratory of Molecular Biology, Howard Hughes Medical Institute, Rockefeller University, New York, 10021 NY, USA, 2Department of Neuropathology, Albert-Ludwigs-University, 79106 Freiburg, Germany, 3Department of Pediatric Neurology and Muscle Disorders, Albert-Ludwigs-University, 79106 Freiburg, Germany, 4Institut für Molekularbiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany and 5Bio-Imaging Resource Center, Rockefeller University, 1230 York Avenue, New York, NY 10021, USA

Received June 1, 2004; Accepted July 9, 2004

Motility of unicellular organisms occurred early in evolution with the emergence of cilia and flagella. In vertebrates, motile cilia are required for numerous functions such as clearance of the airways and determination of left–right body asymmetry. Ependymal cells lining the brain ventricles also carry motile cilia, but their biological function has remained obscure. Here, we show that ependymal cilia generate a laminar flow of cerebrospinal fluid through the cerebral aqueduct, which we term as ‘ependymal flow’. 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 early postnatal brain development. The higher incidence of aqueduct stenosis and hydrocephalus formation in patients with ciliary defects proves the relevance of this novel mechanism in humans.

* To whom correspondence should be addressed. Tel: +49 7612704301; Fax: +49 7612704344; Email: omran{at}kikli.ukl.uni-freiburg.de


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