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Abstract: TH-OR67

Ciliary Exclusion of ARL13B or Loss of Its GEF Activity for ARL3 Suppresses Polycystic Kidney Disease in Mice

Session Information

Category: Genetic Diseases of the Kidneys

  • 1201 Genetic Diseases of the Kidneys: Cystic


  • Van Sciver, Robert E., Emory University School of Medicine, Atlanta, Georgia, United States
  • Caspary, Tamara, Emory University School of Medicine, Atlanta, Georgia, United States

Polycystic kidney disease (PKD) and primary cilia are intricately linked. Mutations in PKD1 and PKD2, which encode for ciliary polycystin proteins, are the most common genetic causes of PKD. Mouse models predict the presence of a cilia-dependent cyst activating (CDCA) pathway that functions in cilia to drive cystogenesis in mouse models of PKD. This CDCA pathway is normally inhibited by the polycystin proteins, yet the ciliary driver(s) of cyst pathogenesis remain unknown. ARL13B is an atypical ciliary GTPase which also possesses guanine nucleotide exchange factor (GEF) activity for another ARL family GTPase, ARL3. Recent work revealed a central role of ARL13B’s cilia localization in cystogenesis, yet its role in the CDCA pathway is unknown.


To directly test ARL13B’s role in the CDCA pathway, we engineered two distinct Arl13b mutant alleles at the endogenous locus in mice: (1) Arl13bV358A, which mutates a single amino acid in ARL13B’s cilia-localization motif; and (2) Arl13bR79Q, which prevents ARL13B’s GEF activity for ARL3. ARL13BV358A retains all known ARL13B biochemical functions, is stably expressed, yet is undetectable in cilia. ARL13BR79Q localizes to cilia, retains its GTPase activity, yet cannot activate ARL3. Using the Pax8rtTA; TetO-Cre system, we induced kidney-specific loss of Pkd1 alone (Pkd1fl/fl) or in combination with either of these alleles (Pkd1fl/fl; Arl13bV358A/fl or Pkd1fl/fl; Arl13bR79Q/fl) in adult mice. This adult induction model allowed us to directly test ARL13B’s ciliary and enzymatic roles in kidney cystogenesis in vivo.


At 18-weeks, control mouse kidneys had a kidney weight to body weight ratio (KW:BW) of 1.39±0.04. In adult induction models, loss of Pkd1 alone led to severe cystic kidneys with KW:BW of 9.71±1.21, while concomitant loss of Pkd1 and ciliary exclusion of ARL13B (V358A) or loss of GEF activity for ARL3 (R79Q) suppressed the cystic phenotype caused by loss of Pkd1 alone with KW:BW of 2.69±0.47 and 2.44±0.43, respectively.


In mouse models, loss of ciliary ARL13B or loss of GEF activity for ARL3 suppressed the severe cystic kidney phenotype caused by loss of Pkd1 alone. These results reveal that ARL13B regulates the CDCA through its GEF activity. Our findings indicate that ARL13B activates a pro-cystogenic pathway, providing a mechanism that could be targeted therapeutically.


  • NIDDK Support