In vivo Analysis of Cell Dynamics of Renal Tubulogenesis in Development and Cystic Kidney Disease

• Applicant: Dr. Soeren Lienkamp
• Subject Area: Nephrology
• Term: from 2014 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 249641671

Cystic kidney disease represents a global health burden, and is the most common genetic cause of end stage renal disease. Renal cysts result from massively dilated tubules that lose or fail to form their elongated and narrow shape. How individual cells arrange into tubules is a fascinating biological problem, and a molecular understanding of this process is highly relevant to the pathology of cystic kidney disease. We previously imaged tubule development in living Xenopus embryos and demonstrated that active cell rearrangements occur during tubule elongation and narrowing. Local myosin activation results in directional cell border motility and cellular rosette formation. In this proposal, we aim to identify molecular components that give direction to tubule formation. We will systematically screen actin/myosin associated proteins for their expression and physiological role during renal tubule formation in Xenopus. Characterization of upstream regulators of localized myosin activation is essential to understand cell rearrangements and cell shape changes. In addition, these regulators are attractive targets for potential intervention strategies. Focusing on proteins that are defective an infantile form of cystic kidney disease (nephronophthisis), we will investigate the role of disease-related proteins in cell rearrangements during tubule morphogenesis. To validate our results in mammals, we will apply the established imaging techniques to kidney cultures of transgenic mice, and directly visualize individual cell movements to analyze how cell rearrangements contribute to renal development and tubule formation. We will use mouse models of nephronophthisis to study the cellular events disrupted in cyst forming tubules. These experiments will reveal how cell movements shape renal tubules during embryonic development, and will identify the molecular mechanism that control cell rearrangement. The expected findings will, provide information about the cyst initiating morphogenetic events. Detailed understanding of the pathogenesis may have significant implications for future treatment strategies of cystic kidney disease.

• DFG Programme: Independent Junior Research Groups