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Kidney Week

Abstract: PO1215

ARL13B Negatively Regulates Kidney Cysts from Within Cilia

Session Information

Category: Genetic Diseases of the Kidneys

  • 1001 Genetic Diseases of the Kidneys: Cystic

Authors

  • Van Sciver, Robert E., Emory University, Atlanta, Georgia, United States
  • Gigante, Eduardo, Emory University, Atlanta, Georgia, United States
  • Caspary, Tamara, Emory University, Atlanta, Georgia, United States
Background

Polycystic kidney disease (PKD) is intricately linked to the primary cilium. Polycystin proteins localize to cilia and loss of cilia leads to renal cysts. PKD mouse models often disrupt ciliary genes, removing both ciliary and cellular pools of these gene products; however, the molecular pathway(s) that drive cyst formation is unknown. ARL13B is a regulatory GTPase highly enriched in cilia due to a VxPx motif near its C terminus. ARL13B is also localized to extraciliary sites within the cell. In most tissues, complete deletion of Arl13b leads to short cilia but in kidney Arl13b deletion leads to a loss of cilia and kidney cysts. As cilia loss leads to renal cysts, it was impossible to determine whether these cysts were due to the loss of cilia or the loss of ARL13B-dependent signaling in cilia. In order to determine the specific function of ARL13B within cilia, we needed a genetic tool that would allow us to isolate the ciliary function of ARL13B.

Methods

We engineered mice in which we mutated the valine to alanine within ARL13B’s VxPx cilia-localization motif so the mice express cilia-excluded ARL13BV358A from the endogenous locus. ARL13BV358A protein retains all known ARL13B biochemical functions, is stably expressed and is undetectable in cilia. We measured renal cysts and cilia phenotypes to functionally characterize the cystic phenotype of cilia-excluded Arl13bV358A/V358A mice.

Results

Arl13bV358A/V358A mice are viable and fertile with slowly progressing renal cysts. Arl13bV358A/+ mice exhibit no cystic phenotypes and Arl13bV358A/null mice develop cysts at a more rapid rate than Arl13bV358A/V358A mice. We detect cysts in all nephron segments of Arl13bV358A/V358A mice. Renal epithelia of Arl13bV358A/V358A mice retain cilia in normal nephrons as well as cystic regions.

Conclusion

Our findings indicate that ARL13B plays a critical role within the cilium in regulating kidney cystogenesis. These results suggest that ARL13B functions as a negative regulator of renal cysts, specifically from within the cilium. Further studies are ongoing to dissect the mechanism(s) by which ciliary ARL13B regulates kidney cystogenesis.

Funding

  • NIDDK Support