Loss of cilia suppresses cyst growth in genetic models of autosomal dominant polycystic kidney disease

Abstract

Kidney cysts occur following inactivation of polycystins in otherwise intact cilia or following complete removal of cilia by inactivation of intraflagellar transport-related proteins. We investigated the mechanisms of cyst formation in these two distinct processes by combining conditional inactivation of polycystins with concomitant ablation of cilia in developing and adult kidney and liver. We found that loss of intact cilia suppresses cyst growth following inactivation of polycystins and that the severity of cystic disease was directly related to the length of time between the initial loss of the polycystin proteins and the subsequent involution of cilia. This cilia-dependent cyst growth was not explained by activation of the MAPK/ERK, mTOR or cAMP pathways and is likely to be distinct from the mechanism of cyst growth following complete loss of cilia. The data establish the existence of a novel pathway defined by polycystin-dependent inhibition and cilia-dependent activation that promotes rapid cyst growth.

Cyst formation following disruption of intracellular calcium signaling

“…A link between ciliary Ca 2+ signaling, the polycystin proteins, and cyst development has recently gained attention (42,(46)(47)(48)(49)(50)(51). The fact that the cilia in the InsP3R3 and PC2 knockdown cysts were still present, but absent in InsP3R1 knockdown cysts, by week 8, suggests that cilia may not be essential to the latter stages of cystogenesis and is broadly consistent with recent findings (52). Our finding that the cilia were no longer observable, and presumably resorbed, when InsP3R1 was knocked down is compatible with the changes associated with the cells undergoing proliferation (see reviews in refs.…”

“…[53][54][55]. However, this latter finding is inconsistent with other studies demonstrating that loss of cilia can halt cyst development after PC1 or PC2 inhibition (52). The strikingly different rate of cyst growth after loss of InsP3R1 suggests that activation of additional pathways contributing to cystogenesis may not be occurring in the cysts arising from loss of PC2 or InsP3R3.…”

Nedd9 restrains renal cystogenesis in Pkd1 −/− mice

“…At present, studies of the role of cilia in cystic syndromes suggest a bifurcated action dependent on the context of the initiating lesion (36)(37)(38)(39). Although loss of cilia due to inactivating mutations in IFT proteins can independently induce cystogenesis, recent strong evidence supports the idea that in the context of lesions in Pkd1 that cause defective signaling from cilia, the removal of cilia suppresses cyst formation (36,37).…”

Cils et kystes rénaux

“…La perte du cil, ou de sa fonction de senseur de flux, conduirait à une dérégulation d'un complexe PC1/mTOR, provoquant une augmentation de la prolifération et de la croissance cellulaires et la formation de kystes, mais indépendamment de la signalisation calcique [39]. Toutefois, des travaux très récents analysant la relation génétique entre polycystines et suppression du cil chez les souris PKD, suggèrent que les voies MAPK (mitogen activated protein kinase)/ERK (extracellular signal-regulated kinase), mTOR et de l'AMPc ne sont que très peu susceptibles d'être à l'origine de signaux de croissance des kystes dépendants du cil [40]. Les auteurs proposent plutôt l'existence de voies divergentes, soit dépendantes des polycystines, soit affectées par la perte du cil.…”

“…Ces observations suggèrent, là encore, que les cils n'ont pas de responsabilité directe dans la formation des kystes congénitaux [30]. Enfin, et de façon inattendue, il semblerait que des cils intacts soient nécessaires à la croissance rapide des kystes après la naissance dans des modèles murins de PKD [40]. En effet, la suppression des cils par l'induction de mutations Kif3A et Ift20 abolit la croissance rapide des kystes chez les souris inactivées pour PC1 ou PC2, indiquant que les cils intacts fournissent un signal positif pour la croissance du kyste, signal réprimé par la fonction normale des polycystines.…”