Polycystin-1 binds Par3/aPKC and controls convergent extension during renal tubular morphogenesis

Abstract

Several organs, including lungs and kidneys, are formed by epithelial tubes whose proper morphogenesis ensures correct function. This is best exemplified by the kidney, where defective establishment or maintanance of tubular diameter results in polycystic kidney disease, a common genetic disorder. Most polycystic kidney disease cases result from loss-of-function mutations in the PKD1 gene, encoding Polycystin-1 (PC-1), a large receptor of unknown function. Here we demonstrate that PC-1 plays an essential role in establishment of correct tubular diameter during nephron development. PC-1 associates with Par3 favoring the assembly of a pro-polarizing Par3/aPKC complex and it regulates a program of cell polarity important for oriented cell migration and for a convergent extension-like process during tubular morphogenesis. Par3 inactivation in the developing kidney results in defective convergent extension and tubular morphogenesis and in renal cyst formation. Our data define PC-1 as central to cell polarization and to epithelial tube morphogenesis and homeostasis.

Disruption of Core Planar Cell Polarity Signaling Regulates Renal Tubule Morphogenesis but Is Not Cystogenic

“…We therefore measured cell number in circumferential cross-sections of tubules over time. As previously described[8, 9], the cross-sectional cell number in wildtype collecting duct and proximal tubules decreases throughout embryonic development, with the most marked reduction occurring between E16.5 and E18.5 (Figure 5A). However, in Vangl2 Lp/Lp mutants, collecting duct cross-sectional cell number decreases more slowly, with the most dramatic difference between mutant and wildtype observed at E17.5, suggesting a maximum perturbation of processes occurring between E16.5 and E17.5.…”

“…PCP dependent CE, while only inferred in mice, is hypothesized to underlie narrowing of tubule diameter and concurrent reduction in the number of cells comprising tubule circumference[8, 9]. We therefore measured cell number in circumferential cross-sections of tubules over time.…”

“…CE has been directly observed by live imaging in the Xenopus nephron[7]. In fixed tissues, CE may be inferred by cellular elongation in the direction of migration, and by this method has been implicated in mouse nephron morphogenesis[8, 9]. Defective inferred CE precedes cystogenesis in Wnt9b [8] and Pkd1 [9] mouse mutant collecting ducts, but the appealing hypothesis that impaired CE leads to cyst formation has not been directly examined.…”

The hallmarks of cancer: relevance to the pathogenesis of polycystic kidney disease

“…Normal PCP signalling, coordinated at the cell cilium [137, 138], is essential for renal morphogenesis, and both ciliary defects and a number of proteins that are intermediaries in PCP signalling have been associated with cystic kidney disorders [139–142]. Polycystin 1 has been specifically linked to the control of PCP signalling [143–145]. …”

Cils et kystes rénaux

“…En revanche, l'allongement du tubule rénal dans le rein du poisson zèbre dépend, lui, de mouvements de migration collective qui activeraient un signal de prolifération et seraient directement dépendants du flux de liquide [51]. Plus récemment, le rôle central de PC1 dans l'acquisition de la polarité cellulaire dans les cellules des canaux collecteurs a été décrit comme essentiel aux mouvements de migration orientée et de convergence-extension, et cela via son interaction avec les complexes de polarité Par3/aPKC (atypical protein kinase C) au cours du développement [52].…”