scholarly journals Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease

2014 ◽  
Vol 124 (6) ◽  
pp. 2315-2324 ◽  
Author(s):  
Peter C. Harris ◽  
Vicente E. Torres
Keyword(s):  
Kidney Disease ◽  
Signaling Pathways ◽  
Polycystic Kidney Disease ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Genetic Mechanisms ◽  
Autosomal Dominant Polycystic Kidney

scholarly journals Loss of polycystins suppresses deciliation via the activation of the centrosomal integrity pathway

2020 ◽  
Vol 3 (9) ◽  
pp. e202000750 ◽  
Author(s):  
Vasileios Gerakopoulos ◽  
Peter Ngo ◽  
Leonidas Tsiokas
Keyword(s):  
Cell Cycle ◽  
Kidney Disease ◽  
Signaling Pathways ◽  
Polycystic Kidney Disease ◽  
Primary Cilia ◽  
Autosomal Dominant ◽  
Polycystic Kidney ◽  
Cyclic Pattern ◽  
Autosomal Dominant Polycystic Kidney ◽  
Cystic Growth

The primary cilium is a microtubule-based, antenna-like organelle housing several signaling pathways. It follows a cyclic pattern of assembly and deciliation (disassembly and/or shedding), as cells exit and re-enter the cell cycle, respectively. In general, primary cilia loss leads to kidney cystogenesis. However, in animal models of autosomal dominant polycystic kidney disease, a major disease caused by mutations in the polycystin genes (Pkd1 or Pkd2), primary cilia ablation or acceleration of deciliation suppresses cystic growth, whereas deceleration of deciliation enhances cystogenesis. Here, we show that deciliation is delayed in the cystic epithelium of a mouse model of postnatal deletion of Pkd1 and in Pkd1- or Pkd2-null cells in culture. Mechanistic experiments show that PKD1 depletion activates the centrosomal integrity/mitotic surveillance pathway involving 53BP1, USP28, and p53 leading to a delay in deciliation. Reduced deciliation rate causes prolonged activation of cilia-based signaling pathways that could promote cystic growth. Our study links polycystins to cilia dynamics, identifies cellular deciliation downstream of the centrosomal integrity pathway, and helps explain pro-cystic effects of primary cilia in autosomal dominant polycystic kidney disease.

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