The Role of Exo 70 in Epithelia Morphogenesis and Renal Tubulogenesis

• Applicant: Dr. Andreas Knödler
• Subject Area: Cell Biology
• Term: from 2008 to 2011
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 90620962

Development of the well-defined renal tubular network is fundamental to kidney function. Epithelia membrane protrusion and migration in response to hepatocyte growth factor (HGF) are the initial pivotal events of tubulogenesis. Aberrant renal tubular structures are major features of Polycystic Kidney Disease (PKD). However, the molecular and cellular basis for tubulogenesis is unclear. Cells extend protrusions by the assembly of a branched actin network that “pushes” the leading edge of the plasma membrane. The Arp2/3 complex is the core machinery that polymerizes actin for the generation of this branched network. Additionally, polarized membrane trafficking is needed for the supply of lipids and proteins to sustain membrane protrusion. The exocyst is a multiprotein complex essential for polarized exocytosis and cell surface expansion during epithelial morphogenesis and renal tubulogenesis. It was recently discovered that Exo70 is a unique component of the exocyst complex that directly interacts with the Arp2/3 and stimulates actin polymerization; the Exo70-Arp2/3 interaction is stimulated by HGF that triggers tubulogenesis. We hypothesize that Exo70 coordinates actin dynamics and membrane traffic during membrane protrusion and plays an important role at the early stages of renal tubulogenesis. Here I propose to investigate the molecular interactions between Exo70 and Arp2/3, and examine the role of Exo70 in membrane protrusion and tubulogenesis in response to HGF stimulation in normal and polycystic kidney disease cells. This study will help us to understand the development of the kidney at the molecular level and guide the future development of therapies for Autosomal Dominant Polycystic Kidney Disease (ADPKD).

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Wei Guo