Borgal, Lori (2013). Wnt Regulation in Cystic Kidney Diseases: Roles for Jade-1, NPHP4, and CK1α. PhD thesis, Universität zu Köln.

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Abstract

Background: Nephronophthisis (NPH) is the leading genetic cause of end-stage renal disease in children, with patients requiring dialysis or kidney transplantation by an average age of 13. Major hallmarks of this disease include interstitial fibrosis, tubular basement membrane disruption, and cyst progression along the cortico-medullary boundary of the kidney. Currently it is not possible to slow or reverse disease progression, and together with other inherited cystic kidney diseases the lack of therapeutic options represents a significant burden for patients and on health care systems. The last decade of research has highlighted the importance of an antenna-like organelle called the primary cilium which is present on virtually all mammalian cells. In the kidney, primary cilia project from the apical surface of kidney epithelial cells into the tubule lumen and are thought to be important for inter-cellular communication required for tissue maintenance. Specifically, primary cilia are involved in the regulation of the Wnt signaling pathway, which is activated during normal injury repair. This work explores the relationship between the gene products mutated in NPH, which localize to the primary cilium, and the regulation of the canonical Wnt signaling pathway by Jade-1, a recently identified ubiquitin ligase for the main effector of canonical Wnt signaling, β-catenin. Main Findings and Conclusions: This work demonstrates that Jade-1 localizes to the ciliary transition zone and interacts with members of the NPH protein complex. Nephrocystin-4 (NPHP4) specifically stabilizes protein levels of Jade-1 in a phosphatase-dependent manner, which increases Jade-1 nuclear translocation and enhances the ability of Jade-1 to negatively regulate canonical Wnt signaling. Jade-1 is phosphorylated by casien kinase-1 α (CK1α), a member of the β-catenin destruction complex, and this abrogates the ability of Jade-1 to negatively regulate Wnt signaling. Exogenous β-catenin decreases protein levels of CK1α and Jade-1 but not NPHP4, which highlights a complex relationship between these proteins. The non-linear nature of Wnt signaling regulation underlines the importance of studying functional protein-protein relationships in context dependent manner. Within the context of published literature, the current data suggests that the cooperative action of NPHP4 and Jade-1 might be most crucial to re-establish noncanonical Wnt signaling immediately following injury repair. Failure of this pathway could contribute to cyst formation in NPH.

Item Type: Thesis (PhD thesis)
Creators:
CreatorsEmailORCID
Borgal, Lorilborgal@gmail.comUNSPECIFIED
URN: urn:nbn:de:hbz:38-54194
Subjects: Natural sciences and mathematics
Uncontrolled Keywords:
KeywordsLanguage
NPHP, kidney, cyst, Jade-1, Wnt, ciliaEnglish
Faculty: Faculty of Mathematics and Natural Sciences
Divisions: Faculty of Mathematics and Natural Sciences > Botanical Institute
Language: English
Date: 15 January 2013
Date of oral exam: 15 January 2013
Referee:
NameAcademic Title
Melkonian, MichaelProf. Dr.
Benzing, ThomasProf. Dr.
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/5419

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