Primary cilia and renal cysts: does length matter?

It is now nearly 400 years since Antonie van Leeuwenhoek noticed the first motile organisms moving by flagella using the earliest microscopes. He would have been surprised to note the fascination that nephrologists have developed with this tiny but versatile organelle over the past 15 years. Flagella appear to be the evolutionarily conserved precursors of both motile and non-motile (or primary) cilia in higher organisms including mammals [1, 2]. It was the recognition that a swimming defective mutant of the biflagellate algae Chlamydomonas reinhardtii was orthologous to an insertional mouse mutant, Tg737 or Oak Ridge Polycystic Kidney (orpk), which provided the critical clue as to the biological importance of cilia [3]. Orpk/Tg737 mice developed polycystic kidneys but also other systemic features now known to be associated with cilia defects such as heterotaxia and retinal and neural tube defects [4]. The orpk mutation was mapped to a gene (Tg737) which encodes for the protein polaris, which in turn is orthologous to the algae protein, intraflagellar transport protein 88 (ift88), identified as essential for cilia assembly (as reviewed in [5]). Intraflagellar transport (IFT) was first observed in Chlamydomonas and shown to be essential for flagellar assembly and maintenance [6]. It is comprised of two multimeric protein complexes, IFT protein complex (‘B’) involved in anterograde cilia transport and a second IFT complex (‘A’) responsible for retrograde transport: IFT88 is a member of Complex B. Mutations in mammalian IFT proteins are now known to be associated with structural defects in cilia and human disease. The phenotype of these ciliary diseases or ‘ciliopathies’ is pleiotropic reflecting the ubiquitous expression of primary cilia by different cell types throughout the body [7]. The localization of the ADPKD proteins, polycystin-1 (PC1) and polycystin-2 (PC2), to primary cilia was the next important clue in directly linking cilia to renal cysts [8]. Unlike IFT mutants, cilia length is normal in PKD1 and PKD2 mutant cells and organisms implying a defect in function rather than structure. Credence was given to this hypothesis by the observation that Pkd1 and Pkd2 mutants in the nematode Caenorhabditis elegans have defects in male mating behaviour, a process known to be dependent on mechanosensation or chemosensation mediated by a small number of ciliated neuronal cells: these mutants expressed structurally normal but functionally defective cilia [9]. The demonstration that the mammalian PC1 and PC2 proteins in kidney epithelia are essential for transducing a cilia-based mechanosensory Ca signal confirmed that polycystin-mediated cilia function was also likely to apply to epithelial cell behaviour [10]. An important difference between PC1 and PC2, however, is the essential requirement for PC2 in embryonic nodal cilia signalling, a function not required for PC1 [11]. We now know that the vast majority of mutated proteins linked to renal cystic diseases can be localized to the primary cilium or its associated structures such as the basal body, centrosomes or ciliary transition zone [12]. There is no doubt that cilia structure, function and stability are all essential for normal kidney development and maintenance. However, it is uncertain that an exclusive ‘cilia hypothesis’ can explain the highly variable renal phenotypic spectrum seen in different diseases, which range from dysplasia to degeneration or fibrosis to cysts [13]. The relative importance of cilia function during organ development as opposed to tissue maintenance in the mature organ has also been debated [14, 15]. In this issue, Mergen et al. report a new mechanism by which cilia disassembly could be regulated by the NPHP2/Inv protein, inversin. Previous work had shown that inversin can act as a flow-activated molecular switch between the canonical and non-canonical Wnt signalling pathways by binding to the common effector protein, Dishevelled (Dvl1), targeting it to the proteasome for degradation [16]. This process can be antagonized by the NPHP8 protein, RPGRIP1L, which forms a complex with both inversin and the NPHP4 protein [17]. In the absence of inversin, canonical Wnt signalling is activated with a concomitant failure to activate non-canonical Wnt activity. The consequences of this would be an increase in cell proliferation with an associated loss of planar cell polarity, likely mechanisms leading to cyst formation. In this latest study, they show that inversin has another function, i.e. it can bind and inhibit the kinase, Aurora A (AurA), which is known to play a pivotal role in regulating cilia stability [18]. AurA IN F O C U S