Mechanismen der Zystogenese: Molekulare Mechanismen der Inversin-Funktion
Final Report Abstract
Our study suggests that the nephronophthisis gene product Inversin is required for migratory processes during early kidney development. In the Xenopus pronephric kidney, this Inversindependent program controls the migration of cells from the dorsal undifferentiated kidney tissue towards a more ventral localization. The simultaneous migration of tubular duct cells from the posterior to the anterior of the kidney, first described in the zebrafish pronephros, is not controlled by Inversin, indicating that Inversin (and perhaps other nephrocystins) may only control specific parts of the developing nephron. During this migration process, the proximal kidney tubule extends, forming the proximal convolution. In the absence of Inversin, the proximal pronephros segments are significantly shortened. Although we did not directly study segmentation, the migratory process is likely accompanied by the differentiation and specification of the proximal nephron segments. The lack of differentiation would explain the development of edema that occurs after depletion of Inversin from both pronephric ducts of the Xenopus embryo. To study the underlying molecular mechanisms, we developed a novel assay system. Using a consecutive injection protocol, we generated mosaic Xenopus animal caps with cells expressing Dishvelled and Frizzled-8 in combination with or without morpholino oligonucleotides targeted against Xenopus Inversin. This assay revealed that Inversin is essential for Frizzled-8 to recruit Dishevelled to the plasma membrane, an essential step in non-canonical (planar cell polarity) Wnt signalling. A rarefication of the proximal tubular segments was also observed in the Inv (-/-) mouse model. Together, these findings suggest that Inversin and perhaps other NPH gene products control morphogenetic programs that facilitate the coordinated migration of tubular epithelial cells and their precursors. Mutation of NPHPs may compromise these programs, resulting in a shortening and incomplete differentiation of these segments, explaining the manifestations of cysts localized at the cortico-medullary border, and the extensive interstitial fibrosis replacing the missing tubular tissue. Furthermore, our findings could also explain the early onset of polyuria due to a concentration defect that often characterizes the onset of nephronophthisis.
Publications
-
Inversin relays Frizzled-8 signals to promote proximal pronephros development. Proc Natl Acad Sci USA. 2010;107(47):20388-93
Lienkamp S, Ganner A, Boehlke C, Schmidt T, Arnold SJ, Schafer T, et al.
-
Inversin, Wnt signaling and primary cilia. Differentiation. 2012;83(2):S49-55
Lienkamp S, Ganner A, Walz G
