Clinical issue

Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of fluid-filled renal cysts that can ultimately lead to organ failure. ADPKD is inherited dominantly by loss-of-function mutations in the PKD1 or PKD2 genes, which encode the human polycystin proteins PC1 and PC2. These two proteins combine to form a heterodimeric TRP (transient receptor potential)-family cation channel that localizes to sensory cilia in the renal epithelium. These channels are necessary for the flow-sensing ability of kidney cells. ADPKD pathology is thought to arise through a cellular-recessive mechanism in which the disruption of one allele of either PKD1 or PKD2 predisposes a cell to the somatic loss of the remaining functional allele. When this occurs, the current models of ADPKD hold that compromised flow sensing disrupts homeostasis in the renal epithelium, increasing cell proliferation and inducing the formation of cysts.


In C. elegans, the polycystins LOV-1 (PC1) and PKD-2 (PC2) act in the ciliated endings of male sensory neurons to transduce signals that are important for the execution of mating behavior. In the current work, the authors identify CWP-5, a novel single-pass membrane protein that colocalizes with the polycystins to a characteristic set of male-specific sensory neurons. Males carrying cwp-5 mutations show significant defects in initiating mating behavior, a phenotype reminiscent of lov-1 and pkd-2 mutants. Genetic interactions between cwp-5 and the polycystins indicate that cwp-5 acts in the polycystin signaling pathway. However, these studies also reveal that LOV-1 and PKD-2 can interfere with sensory behavior in mutants lacking both cwp-5 and a single polycystin. CWP-5 may normally repress interference by preventing toxic polycystin forms from reaching the cilia and/or by blocking their aberrant properties in the cilium itself.

Implications and future directions

These genetic interactions between CWP-5 and the C. elegans polycystins raise the possibility that the dominant view of ADPKD, in which cystogenesis results from the loss of polycystin function, may not adequately account for its pathogenesis. Instead, cells lacking PKD1 or PKD2 may also suffer from unmasked deleterious properties of the mutant polycystin. There are also intriguing parallels between CWP-5 and fibrocystin/polyductin (FPC), the ciliary protein linked to autosomal recessive polycystic kidney disease, that lead to more speculative suggestions about how aberrant polycystin functions could also contribute to ARPKD. Both of these ideas imply that interventions to block aberrant polycystin properties could have therapeutic value in polycystic kidney disease. Further studies in mice, where polycystic kidney disease pathology can be modeled more faithfully, will be important for testing the predictions of this toxic polycystin model.