Document Detail


Loss of the ciliary kinase Nek8 causes left-right asymmetry defects.
MedLine Citation:
PMID:  23274954     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Danielle K Manning; Mikhail Sergeev; Roy G van Heesbeen; Michael D Wong; Jin-Hee Oh; Yan Liu; R Mark Henkelman; Iain Drummond; Jagesh V Shah; David R Beier
Related Documents :
25006744 - Genome-wide association identifies regulatory loci associated with distinct local histo...
17339204 - Caenorhabditis elegans mutants resistant to attachment of yersinia biofilms.
24218264 - Functional evaluation of factor h genetic and acquired abnormalities: application for a...
12597434 - The state of the art of the zebrafish model for toxicology and toxicologic pathology re...
17534404 - The association of hla-drb1 alleles with rheumatoid arthritis in the chinese shantou po...
19619024 - Seasonal changes in the genetic structure of an aphid-ant mutualism as revealed using m...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Journal of the American Society of Nephrology : JASN     Volume:  24     ISSN:  1533-3450     ISO Abbreviation:  J. Am. Soc. Nephrol.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-31     Completed Date:  2013-03-04     Revised Date:  2014-01-09    
Medline Journal Info:
Nlm Unique ID:  9013836     Medline TA:  J Am Soc Nephrol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  100-12     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Biological Markers / 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*,  metabolism
TRPP Cation Channels / metabolism
Zebrafish
Grant Support
ID/Acronym/Agency:
P50 DK074030/DK/NIDDK NIH HHS; R01 DK053093/DK/NIDDK NIH HHS; R01 DK66370/DK/NIDDK NIH HHS
Chemical
Reg. No./Substance:
0/Biological Markers; 0/TRPP Cation Channels; 0/polycystic kidney disease 2 protein; EC 2.7.11.1/Nek8 protein, mouse; EC 2.7.11.1/Protein-Serine-Threonine Kinases
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


Previous Document:  p-Cresyl sulfate promotes insulin resistance associated with CKD.
Next Document:  Agalsidase benefits renal histology in young patients with Fabry disease.