title: 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 6weeks of age and exhibit dilation of the lateral and third ventricles leading to fatal acquired hydrocephalus by ~5months 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.
authors: Terry Fox Molecular Oncology Group and the Bloomfield Center for Research on Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec H3T1E2, Canada.
authors: Christina
authors: C
authors: Gavino
authors: Stéphane
authors: S
authors: Richard
mesh_terms: D000818:Animals; D002552:Cerebral Ventricles / Q000033:anatomy & histology; D002923:Cilia / Q000378:metabolism* / Q000473:pathology; D004805:Ependyma / Q000166:cytology* / Q000378:metabolism; D057895:Haploinsufficiency; D006849:Hydrocephalus / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008821:Mice, Quaking; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011956:Receptors, Cell Surface / Q000172:deficiency / Q000235:genetics*; D015996:Survival Rate
chemical_list: D000072079:Patched Receptors; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface