ZFIN ID: ZDB-PUB-130108-4
Loss of the ciliary kinase nek8 causes left-right asymmetry defects
Manning, D.K., Sergeev, M., van Heesbeen, R.G., Wong, M.D., Oh, J.H., Liu, Y., Henkelman, R.M., Drummond, I., Shah, J.V., and Beier, D.R.
Date: 2013
Source: Journal of the American Society of Nephrology : JASN   34(1): 100-112 (Journal)
Registered Authors: Beier, David R., Drummond, Iain, Liu, Yan
Keywords: none
MeSH Terms:
  • Animals
  • Biomarkers/metabolism
  • Body Patterning*
  • Cilia/physiology*
  • Disease Models, Animal
  • Female
  • Heart Defects, Congenital/embryology
  • Heterozygote
  • Homozygote
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phenotype
  • Polycystic Kidney Diseases/genetics*
  • Protein-Serine-Threonine Kinases/genetics*
  • Protein-Serine-Threonine Kinases/metabolism
  • TRPP Cation Channels/metabolism
  • Zebrafish
PubMed: 23274954 Full text @ J. Am. Soc. Nephrol.

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.