Patched1 haploinsufficiency impairs ependymal cilia function of the quaking viable mice, leading to fatal hydrocephalus

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• 作者：Christina Gavino^a ; ^b ; ^c ; Sté ; phane Richard ; ^a ; ^b ; ^c ; ^{stephane.richard@mcgill.ca"" rel=""nofollow}
• 关键词：Hydrocephalus ; Patched1 ; Quaking viable mice ; Cilia
• 刊名：Molecular and Cellular Neuroscience
• 出版年：2011
• 出版时间：June 2011
• 年：2011
• 卷：47
• 期：2
• 页码：100-107
• 全文大小：1599 K

文摘

The quaking viable (qk^v) mice harbor an autosomal recessive mutation that deletes the parkin co-regulated gene (pacrg) and parkin (park2) genes, and alters the expression of the quaking (qkI) gene. qk^v mice have been well-studied for their dysmyelination phenotype caused by the altered expression of the qkI gene. The qk^v mice exhibit sterility in males and develop acquired mild hydrocephalus due to the lack of PACRG expression. To identify genetic interactors of the pacrg–parkin–qkI locus, we crossbred the qk^v mice with various mouse strains including the patched1 (ptch1)-deficient mice. The ptch1 heterozygous mice exhibit increased Sonic Hedgehog (Shh) signaling and are prone to several malignancies including tumorigenesis. In the present study, we show that the qk^v/v; ptch1^+/− mice are distinguished by a dome-shaped skull at 4 to 6 weeks of age and exhibit dilation of the lateral and third ventricles leading to fatal acquired hydrocephalus by ~ 5 months of age, unlike their littermate controls that did not develop the condition. The qk^v/v; ptch1^+/− mice contained normal ciliated ependymal cells lining the ventricles of the brain, but these cells were functionally compromised with a severe cilial mediated flow defect. Our findings suggest that the ptch1 and the pacrg–parkin–qkI loci genetically interact to regulate cilia function of the ependymal cells.