PKD2 encodes a transient receptor potential polycystin (TRPP) channel receptor protein found in non-motile, primary cilia of mammalian cells 1. In humans, PKD2 mutations result in Autosomal Dominant Polycystic Kidney Disease (ADPKD). In the nematode Caenorhabditis elegans, the polycystin-2 homolog, PKD-2, localizes to the primary cilia of male-specific sensory neurons (CEMs and RnBs in the head and tail respectively) where it is required for male mating behaviors. Given the ancient and evolutionarily conserved role for polycystin-2 in cilia, I am using C. elegans as a model to identify new genes required for ciliary receptor localization. Our laboratory performed a forward genetic screen for PKD-2::GFP ciliary localization (Cil) defective mutants (Bae et al 2008). The cil-2
) mutants exhibit excess unusual PKD-2 accumulation at the ciliary base, cilium proper, and around the distal dendrite. We performed three-factor and deficiency mapping, whole genome sequencing, and single gene rescue experiments and determined that the cil-2
) allele is a mutation in the gene, mec-5
. MEC-5 is a unique collagen protein found in the extracellular matrix (ECM) surrounding touch receptor neurons (Du et al 1996). In touch receptor neurons (TRNs), MEC-1, MEC-5, and MEC-9 are found in the ECM, play a role in mechanosensation, and may localize degenerin/epithelial sodium channels (DEG/ENaCs) along the TRN processes (Du et al 1996, Emtage et al 2004). Our preliminary data indicates that mec-1
regulate PKD-2::GFP localization in male-specific sensory neurons. We are currently determining how these ECM proteins regulate localization and channel properties of the PKD-2 TRP polycystin channel. These studies will shed light on how sensory receptors like PKD-2 are targeted to cilia, and may advance the understanding and treatment of ADPKD. References: 1) Bae YK et al, Dev Dyn. 2008 Aug;237(8):2021-9. 2) Du H. et al, Neuron. 1996 Jan;16(1):183-94. 3) Emtage L et al, Neuron. 2004 Dec 2;44(5):795-807.