title: 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, kidney-specific 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.
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Jonassen
authors.forename: Jovenal
authors.initials: J
authors.lastname: SanAgustin
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Baker
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Pazour
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D002923:Cilia / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006801:Humans; D052177:Kidney Diseases, Cystic / Q000235:genetics* / Q000378:metabolism; D007685:Kidney Tubules, Collecting / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D008938:Mitosis; D012333:RNA, Messenger / Q000032:analysis; D011897:Random Allocation; D015398:Signal Transduction / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D051153:Wnt Proteins