Disruption of IFT Complex A Causes Cystic Kidneys without Mitotic Spindle Misorientation

Abstract

Intraflagellar transport (IFT) complexes A and B build and maintain primary cilia. In the mouse, kidneyspecific or hypomorphic mutant alleles of IFT complex B genes cause polycystic kidneys, but the influence of IFT complex A proteins on renal development is not well understood. In the present study, we found that HoxB7-Cre-driven deletion of the complex A gene Ift140 from collecting ducts disrupted, but did not completely prevent, cilia assembly. Mutant kidneys developed collecting duct cysts by postnatal day 5, with rapid cystic expansion and renal dysfunction by day 15 and little remaining parenchymal tissue by day 20. In contrast to many models of polycystic kidney disease, precystic Ift140-deleted collecting ducts showed normal centrosomal positioning and no misorientation of the mitotic spindle axis, suggesting that disruption of oriented cell division is not a prerequisite to cyst formation in these kidneys. Precystic collecting ducts had an increased mitotic index, suggesting that cell proliferation may drive cyst expansion even with normal orientation of the mitotic spindle. In addition, we observed significant increases in expression of canonical Wnt pathway genes and mediators of Hedgehog and tissue fibrosis in highly cystic, but not precystic, kidneys. Taken together, these studies indicate that loss of Ift140 causes pronounced renal cystic disease and suggest that abnormalities in several different pathways may influence cyst progression.

Downregulating Hedgehog Signaling Reduces Renal Cystogenic Potential of Mouse Models

“…23 Thus, data from five mouse models-IFT140, 23 Glis2, 15 Thm1, jck, and Pkd1-suggest elevated Hh signaling in cystic kidneys. Additionally, a global gene expression analysis of kidneys from patients with ADPKD revealed increased expression of Hh signaling components, including GLI2, Ptch1, and GAS1.…”

“…23 However, THM1 mutations have been reported in 5% of patients with ciliopathies, rendering THM1 the most commonly mutated gene in ciliopathies 24 and thereby implicating this gene in renal disease. We investigated the consequences of Thm1 deletion in renal cystogenesis using the Thm1 aln/aln developmental mutant and a newly developed Thm1 conditional knockout mouse.…”

Context-Dependent Regulation of Wnt Signaling through the Primary Cilium

“…[1][2][3] Although once considered a vestigial structure, the recent association of ciliary dysfunction with a host of genetic disorders known collectively as ciliopathies 2 has highlighted an array for roles for this organelle critical for both development and homeostasis. In the kidney, dysfunction of primary cilium results in a variety of ciliopathies 4 and modulates cystogenesis [5][6][7][8] and planar cell polarity (PCP). 6,9,10 An emerging class of functions involves signaling receptors and/or effectors delivered to the ciliary axoneme by specialized transport machinery and sequestered to regulate morphogenetic signaling pathways.…”

Cils et kystes rénaux

“…La question du lien de cette orientation dans le rein reste actuellement controversé. Même si IFT88 est directement impliquée dans ce processus, les résultats diffèrent selon les IFT étudiées [17,18]. Le rôle du cil dans la régula-tion des voies de polarité planaire pourrait passer par le contrôle de la maturation et de la position du centrosome dans l'établissement du fuseau mitotique [47].…”

“…Les mutants conditionnels Kif3a, dont les dérivés du bourgeon urétéral sont dépourvus de cils, se caractérisent par des réductions de l'arborescence que corrige l'expression de la forme Gli3R constitutive, soulignant le rôle du cil dans la signalisation Hh éga-lement dans le rein [30]. De plus, les délétions de Thm1 (TPR-containing Hedgehog modulator 1)-Ift139 et Ift140 altèrent la formation des cils au cours de l'embryogenèse chez la souris, provoquent des kystes rénaux et s'accompagnent d'une augmentation des transcrits Gli et de la signalisation Hh, faisant le lien entre voies Hh, cils et kystes rénaux [18,55]. Les souris mutantes Mks1 présentent, outre des kystes glomérulaires et tubulaires congénitaux, des anomalies urétérales qui pourraient résulter d'un dysfonctionnement de la voie Shh [10].…”