Towards Understanding the Polycystins

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is a very common inherited disease caused by mutations in <i>PKD1 </i>or <i>PKD2</i> genes characterized by progressive enlargement of fluid-filled cysts and loss of renal function [<citeref rid="ref001">1</citeref>]. Previous studies proposed a role for human polycystin-1 in renal morphogenesis acting as a matrix receptor in focal adhesions and for polycystin-2 as a putative calcium channel [<citeref rid="ref002">2</citeref>, <citeref rid="ref003">3</citeref>]. The genome of <i>Caenorhabditis elegans</i> contains 2 new members of the polycystin family: <i>lov-1</i>, the homolog for <i>PKD1</i>; and <i>pkd-2</i>, the homolog for <i>PKD2</i> [<citeref rid="ref004">4</citeref>; this paper]. Mutation analysis in <i>C. elegans</i> showed similarly compromised male mating behaviors in all single and double <i>lov-1</i> and <i>pkd-2</i> mutants, indicating their participation in a single genetic pathway. Expression analysis localized LOV-1 and PKD-2 to the ends of sensory neurons in male tails and to the tips of CEM neurons in the head, consistent with functions as chemo- or mechanosensors. Human and <i>C. elegans PKD1</i> and <i>PKD2</i> homologs, transfected into mammalian renal epithelial cells, co-localized with paxillin in focal adhesions suggesting function in a single biological pathway. Based on the role of polycystins in <i>C. elegans</i> sensory neuron function and the conservation of PKD pathways we suggest that polycystins act as sensors of the extracellular environment, initiating, via focal adhesion assembly, intracellular transduction events in neuronal or morphogenetic processes.