Funktionale Analyse des Cdh1-APC/SnoN Signaltransduktionsweges im axonalen Wachstum und der Musterbildung des zentralen Nervensystems

点击翻译按钮获取中文摘要

Axon growth is an essential event that ensures the proper wiring and connectivity of the brain. Hence, it is important to understand the underlying mechanisms that govern axon growth. Considerable progress has been made in characterizing extrinsic factors such as guidance cues, however little is known about intrinsic programs regulating axon growth. Increasing evidence however suggests that the ubiquitin proteasome system (UPS) is crucial to axonal growth. The E3 ubiquitin ligase Cdh1-APC is an important cell cycle regulator. Surprisingly, Cdh1-APC is expressed in postmitotic neurons. We found that Cdh1-APC acts as an intrinsic repressor of axonal growth and regulates patterning in the cerebellum. In addition, we identified the transcriptional cofactor SnoN as a key target of Cdh1-APC in axon growth regulation. To delineate the Cdh1-APC/SnoN pathway, we will address the following questions. (1) What is the underlying mechanism of SnoN-mediated axonal growth? (2) Is there crosstalk between the Cdh1-APC/SnoN pathway and known mechanisms of axonal growth regulation? (3) Which neuronal targets of Cdh1-APC control patterning in the mammalian brain? We will use the rodent brain as model system and apply cell and molecular biological, and biochemical techniques, in vitro and in vivo studies, proteomics, and transcripteomics.