Deletion of the Parkin co-regulated gene causes defects in ependymal ciliary motility and hydrocephalus in the quakingviable mutant mouse

Gabrielle R Wilson, Hong X Wang, Gary F Egan, Philip J Robinson, Martin B Delatycki, Moira K O'Bryan, Paul J Lockhart

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Abstract

The quaking(viable) mouse (qk(v)) is a spontaneous recessive mouse mutant with a deletion of approximately 1.1Mb in the proximal region of chromosome 17. The deletion affects the expression of three genes; quaking (Qk), Parkin-coregulated gene (Pacrg) and parkin (Park2). The resulting phenotype, which includes dysmyelination of the CNS and male sterility, is due to reduced expression of Qk and a complete lack of Pacrg expression, respectively. Pacrg is required for correct development of the spermatozoan flagella, a specialised type of motile cilia. In vertebrates, motile cilia are required for multiple functions related cellular movement or movement of media over a stationary cell surface. To investigate the potential role of PACRG in motile cilia we analysed qk(v) mutant mice for evidence of cilial dysfunction. Histological and MRI analyses demonstrated that qk(v) mutant mice were affected by acquired, communicating hydrocephalus. Structural analysis of ependymal cilia demonstrated that the 9+2 arrangement of axonemal microtubules was intact and that both the density of ciliated cells and cilia length was similar to wildtype littermates. Cilia function studies showed a reduction in ependymal cilial beat frequency and cilial mediated flow in qk(v) mutant mice compared to wildtype littermate controls. Moreover, transgenic expression of Pacrg was necessary and sufficient to correct this deficit and rescue the hydrocephalus phenotype in the qk(v) mutant. This study provides novel in vivo evidence that Pacrg is required for motile cilia function and may be involved in the pathogenesis of human ciliopathies, such as hydrocephalus, asthenospermia and primary ciliary dyskinesia.
Original languageEnglish
Pages (from-to)1593 - 1602
Number of pages10
JournalHuman Molecular Genetics
Volume19
Issue number8 (Art. No. ddq031)
DOIs
Publication statusPublished - 2010

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