title: Loss of the ciliary kinase Nek8 causes left-right asymmetry defects.
abstract: A missense mutation in mouse Nek8, which encodes a ciliary kinase, produces the juvenile cystic kidneys (jck) model of polycystic kidney disease, but the functions of Nek8 are incompletely understood. Here, we generated a Nek8-null allele and found that homozygous mutant mice die at birth and exhibit randomization of left-right asymmetry, cardiac anomalies, and glomerular kidney cysts. The requirement for Nek8 in left-right patterning is conserved, as knockdown of the zebrafish ortholog caused randomized heart looping. Ciliogenesis was intact in Nek8-deficient embryos and cells, but we observed misexpression of left-sided marker genes early in development, suggesting that nodal ciliary signaling was perturbed. We also generated jck/Nek8 compound heterozygotes; these mutants developed less severe cystic disease than jck homozygotes and provided genetic evidence that the jck allele may encode a gain-of-function protein. Notably, NEK8 and polycystin-2 (PC2) proteins interact, and we found that Nek8(-/-) and Pkd2(-/-) embryonic phenotypes are strikingly similar. Nek8-deficient embryos and cells did express PC2 normally, which localized properly to the cilia. However, similar to cells lacking PC2, NEK8-depleted inner medullary collecting duct cells exhibited a defective response to fluid shear, suggesting that NEK8 may play a role in mediating PC2-dependent signaling.
authors.affiliation: Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Danielle K
authors.initials: DK
authors.lastname: Manning
authors.forename: Mikhail
authors.initials: M
authors.lastname: Sergeev
authors.forename: Roy G
authors.initials: RG
authors.lastname: van Heesbeen
authors.forename: Michael D
authors.initials: MD
authors.lastname: Wong
authors.forename: Jin-Hee
authors.initials: JH
authors.lastname: Oh
authors.forename: Yan
authors.initials: Y
authors.lastname: Liu
authors.forename: R Mark
authors.initials: RM
authors.lastname: Henkelman
authors.forename: Iain
authors.initials: I
authors.lastname: Drummond
authors.forename: Jagesh V
authors.initials: JV
authors.lastname: Shah
authors.forename: David R
authors.initials: DR
authors.lastname: Beier
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D019521:Body Patterning; D002923:Cilia / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006330:Heart Defects, Congenital / Q000196:embryology; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000072379:NIMA-Related Kinases; D010641:Phenotype; D007690:Polycystic Kidney Diseases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D050396:TRPP Cation Channels / Q000378:metabolism; D015027:Zebrafish
chemical_list: D015415:Biomarkers; D000072379:NIMA-Related Kinases; D017346:Protein Serine-Threonine Kinases; D050396:TRPP Cation Channels; C499219:Nek8 protein, mouse