Home
P 18 - Prof. Dr. Gerd Walz
The role of formins as down-stream effector molecules of nephrocystins
Prof. Dr. Gerd Walz Medizinische Klinik IV Hugstetter Str. 55 79106 Freiburg Phone: +49 761 270-3250 Fax: +49 761 270-3245 gerd.walz@uniklinik-freiburg.de
| |
Project Summary
Nephronophthisis (NPH) is a heterogenetic autosomal recessive disease associated with kidney cysts and multiple extrarenal manifestations. More than a dozen of NPH genes have been identified, and most NPH genes products (NPHPs) localize to the cilium, where they form networks to restrict the access of molecules to the ciliary compartment. However, NPHPs have also been implicated in other, seemingly unrelated functions including cell-cell contacts and migration as well as Wnt and Hippo signaling. Our preliminary work indicates that several NPH family members interact with formins, a group of actin-modifying proteins. Formins might therefore represent crucial down-stream effector molecules, which organize the actin cytoskeleton in response to NPHPs. To substantiate this hypothesis, we will determine whether NPHPs can recruit and activate formins to modify the local actin environment, and examine whether formins together with NPHPs act in cellular signaling pathways. To further test the concept that NPHPs exert their molecular functions through changes in actin polymerization, we will examine whether depletion of NPHP-interacting formins cause NPH-typical manifestations in NPH animal models and synergize with NPHPs to enhance disease severity. Finally, we will define the composition and localization of NPHP-formin networks using mass spectrometry and high-resolution imaging, and analyze their dynamics by time-lapse confocal microscopy. Collectively, the results will help to explain how NPHPs participate in diverse cellular programs, including ciliogenesis, cell polarity, cell migration and developmental signaling programs. | |