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First published online November 10, 2005
doi: 10.1242/10.1242/dev.02153

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Dysfunctional cilia lead to altered ependyma and choroid plexus function, and result in the formation of hydrocephalus

¹ Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
² Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL 35294, USA
³ High Resolution Imaging Facility, University of Alabama at Birmingham, Birmingham, AL 35294, USA
⁴ Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
⁵ Nephrology Research and Training Center, University of Alabama at Birmingham, Birmingham, AL 35294, USA
⁶ Department of Physiology and Biophysics, University of Alabama at Birmingham, Birmingham, AL 35294, USA

^* Author for correspondence (e-mail: byoder{at}uab.edu)

Accepted 7 October 2005

Cilia are complex organelles involved in sensory perception and fluid or cell movement. They are constructed through a highly conserved process called intraflagellar transport (IFT). Mutations in IFT genes, such as Tg737, result in severe developmental defects and disease. In the case of the Tg737^orpk mutants, these pathological alterations include cystic kidney disease, biliary and pancreatic duct abnormalities, skeletal patterning defects, and hydrocephalus. Here, we explore the connection between cilia dysfunction and the development of hydrocephalus by using the Tg737^orpk mutants. Our analysis indicates that cilia on cells of the brain ventricles of Tg737^orpk mutant mice are severely malformed. On the ependymal cells, these defects lead to disorganized beating and impaired cerebrospinal fluid (CSF) movement. However, the loss of the cilia beat and CSF flow is not the initiating factor, as the pathology is present prior to the development of motile cilia on these cells and CSF flow is not impaired at early stages of the disease. Rather, our results suggest that loss of cilia leads to altered function of the choroid plexus epithelum, as evidenced by elevated intracellular cAMP levels and increased chloride concentration in the CSF. These data suggest that cilia function is necessary for regulating ion transport and CSF production, as well as for CSF flow through the ventricles.

Key words: Cilia, Hydrocephalus, Tg737, Intraflagellar transport, Choroid plexus, Ependyma

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