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

轴突生长是确保大脑正确连接和连接的重要事件。因此，了解支配轴突生长的潜在机制是很重要的。在表征引导线索等外在因素方面已经取得了相当大的进展，然而关于调控轴突生长的内在程序却知之甚少。然而，越来越多的证据表明，泛素蛋白酶体系统(UPS)对轴突生长至关重要。E3泛素连接酶CDH1-APC是一种重要的细胞周期调节因子。令人惊讶的是，CDH1-APC在有丝分裂后神经元中表达。我们发现，CDH1-APC作为轴突生长的内在抑制因子，调节小脑的模式。此外，我们还发现转录辅助因子SnoN是CDH1-APC调控轴突生长的关键靶点。为了描述CDH1-APC/SnoN通路，我们将解决以下问题。(1)SnoN介导的轴突生长的潜在机制是什么？(2)CDH1-APC/SnoN通路与已知的轴突生长调节机制之间是否存在串扰？(3)CDH1-APC的哪些神经元靶点控制着哺乳动物大脑中的模式？我们将以啮齿动物脑为模型系统，应用细胞和分子生物学、生化技术、体外和体内研究、蛋白质组学和转录组学。

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.