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Cilia and cyst formation: guilt by association

A convergence of data suggests that cilia are important in the pathogenesis of PKD. Despite intense investigation, the precise nature of this relationship remains unclear. It has been suggested that the the PKD1/PKD2 receptor channel complex acts as a flow sensor on renal epithelial cells. When this complex is inactivated (for any reason), cyst formation occurs. However, disruption of TRPV4 in MDCK cells results in absence of flow mediated signaling yet TRPV4 Knock out mice do not develop cysts. We need to understand the precise relationship of cilia to cystogenesis.

Comment

Submitted by Terry Watnick 3 years ago

Comments (5)

  1. I definitely agree with Terry's comment. The idea of cilia and cystogenesis sounds great, but there is a big black hole that we need to work on to understand the relationship between cilia to cystogenesis.

    3 years ago
  2. I think there is little doubt on the role of cilia in PKD. However, there is no evidence conencting specifically the ciliary pool of PKD1/2 to any cellular function, at least in mammalian cells. One reason for this is perhaps dificulties in studying PKD1/2 function at the cilium and/or basal body/centrosome. Therefore, I see here the need to develop the tools and technology to study Ca2+ signaling specifically in these organelles, as conventional methods such as patch clamp, fura/fluo-based fluorescence etc cannot be applicable or difficult to work.

    leo

    3 years ago
  3. I agree with the posted comments that further in-depth understanding of the roles of cilia in PKD lies in connecting the ciliary pool of PKD1/PKD2 to cellular functions. The black box here concerns with what happens next after Pkd2-mediated calcium influx on the cilium. Due to high concentrations of calcium binding proteins in most cell types, it is generally thought that calcium rise in the cilium proper would not directly lead to calcium rise in the cell body. In other words, there must be intermediary steps between Pkd2-mediated calcium influx within the cilium and effector proteins/pathways located in the cell body. Giving that the role of cilium in PKD is now well established, the next important task is to identify these intermediary steps. - Xiangyi

    3 years ago
  4. I agree with the other comments, and am glad there is a consensus about a need for addressing what the primary cilium does for a living. Despite the fact that the different players have been placed, there is no clear link between say ciliary PC2 function and ciliary structure. The techniques are now becoming available to address issues of ciliary function that go beyond showing whether the cilium changes in shape. It is important to note that calcium entry in the primary cilium may be essential for its size and structure. This could be a potentially relevant following step.

    3 years ago
  5. I agree with the need for new technologies to analyze the specific functions of the proteins in the cilia. Whole cell assays are inadequate. We need better ways for looking at specific subpopulations and assemblies of proteins that are defined by their locations and unique functions in those locations.

    3 years ago

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