A role for NPH proteins in controlling Hippo signaling - Novel clues to the pathogenesis of Nephronophthisis

• Applicant: Professor Dr. Bernhard Schermer
• Subject Area: Nephrology
• Term: from 2013 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 235379065

Nephronophthisis (NPH) is an autosomal recessive cystic kidney disease that constitutes the most frequent genetic cause for end-stage renal disease (ESRD) in children and young adults. In contrast to other renal cystic diseases kidney size in NPH appears normal or even reduced. Mutations of 12 genes (NPHP1-12) that encode for the heterogeneous nephrocystine protein family have been identified as causative for this progressive disorder. The function of these genes, however, is not well understood. The gene products predominantly localize to primary cilia together with their basal bodies/centrioles of renal tubular cells. Cilia are microtubule (MT)-based antenna-like organelles which extend from the surface of almost all cell types of the human body. The ciliary axoneme emerges from the basal body, a modified centriole that also functions as the spindle-organizing center in mitosis. In the kidney, cilia project from the apical surface of tubular epithelial cells into the lumen of the kidney tubules. As sensory organelles they transmit signals from the lumen to the inside of the tubular cells. Previous work of our group identified NPH proteins as regulators of the hippo signaling pathway. This pathway was first described in Drosophila melanogaster and has gained increasing attention since it was shown to control cell proliferation and organ size in a highly conserved manner and to be involved in tumorigenesis. The overarching goal of this project is to understand the function of the hippo signaling pathway in the molecular pathogenesis of NPH and to uncover its contribution to additional cystic kidney diseases with a focus on hippo signaling as a potential target of future therapeutic strategies. In this project we will (1) investigate the mechanism underlying the regulation of Hippo signaling through NPH proteins and additional ciliary, cystogenic proteins and study the connection of cilia and hippo signaling, (2) identify the hippo-dependent transcriptional targets regulated through NPHs and ciliary proteins, and (3) analyze the role of deregulated hippo signaling in vivo in different mouse models of cystic kidney disease with specific emphasis on potential therapeutic options.

• DFG Programme: Research Grants