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

Abstract 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.