title: Endothelial cilia are essential for developmental vascular integrity in zebrafish.
abstract: The cilium is a signaling platform of the vertebrate cell. It has a critical role in polycystic kidney disease and nephronophthisis. Cilia have been detected on endothelial cells, but the function of these organelles in the vasculature remains incompletely defined. In this study, using genetic and chemical genetic tools in the model organism zebrafish, we reveal an essential role of cilia in developmental vascular integrity. Embryos expressing mutant intraflagellar transport genes, which are essential and specific for cilia biogenesis, displayed increased risk of developmental intracranial hemorrhage, whereas the morphology of the vasculature remained normal. Moreover, cilia were present on endothelial cells in the developing zebrafish vasculature. We further show that the involvement of cilia in vascular integrity is endothelial autonomous, because endothelial-specific re-expression of intraflagellar transport genes in respective mutants rescued the intracranial hemorrhage phenotype. Finally, whereas inhibition of Hedgehog signaling increased the risk of intracranial hemorrhage in ciliary mutants, activation of the pathway rescued this phenotype. In contrast, embryos expressing an inactivating mutation in pkd2, one of two autosomal dominant cystic kidney disease genes, did not show increased risk of developmental intracranial hemorrhage. These results suggest that Hedgehog signaling is a major mechanism for this novel role of endothelial cilia in establishing vascular integrity.
authors.affiliation: Department of Genetics and.
authors.forename: Sowjanya
authors.initials: S
authors.lastname: Kallakuri
authors.affiliation: Program in the Genomics of Differentiation, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jianxin A
authors.initials: JA
authors.lastname: Yu
authors.affiliation: Department of Genetics and.
authors.forename: Jade
authors.initials: J
authors.lastname: Li
authors.affiliation: Department of Genetics and.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Program in the Genomics of Differentiation, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland.
authors.forename: Brant M
authors.initials: BM
authors.lastname: Weinstein
authors.affiliation: Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut; and.
authors.forename: Stefania
authors.initials: S
authors.lastname: Nicoli
authors.affiliation: Department of Genetics and zhaoxia.sun@yale.edu.
authors.forename: Zhaoxia
authors.initials: Z
authors.lastname: Sun
mesh_terms: D000818:Animals; D002923:Cilia / Q000502:physiology*; D042783:Endothelial Cells / Q000166:cytology; D004730:Endothelium, Vascular / Q000502:physiology*; D053823:Hedgehog Proteins / Q000378:metabolism*; D020300:Intracranial Hemorrhages / Q000209:etiology*; D040542:Mechanotransduction, Cellular; D050396:TRPP Cation Channels / Q000502:physiology; D015027:Zebrafish
chemical_list: D053823:Hedgehog Proteins; D050396:TRPP Cation Channels
keywords: cystic kidney; endothelium; signaling; vascular disease