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布线和连接的重要事件。因此，重要的是要了解支配轴突生长的潜在机制。已经取得了相当大的进展，在表征外在因素，如指导线索，但鲜为人知的是内在程序调节轴突生长。然而，越来越多的证据表明，泛素蛋白酶体系统（UPS）是至关重要的轴突生长。E3泛素连接酶Cdh 1-APC是一种重要的细胞周期调节因子。令人惊讶的是，Cdh 1-APC在有丝分裂后的神经元中表达。我们发现，Cdh 1-APC作为一个内在的轴突生长抑制剂，并调节小脑的图案。此外，我们确定了转录辅因子SnoN作为Cdh 1-APC在轴突生长调节中的关键靶点。为了描述Cdh 1-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)Cdh 1-APC/SnoN通路和已知的轴突生长调节机制之间是否存在串扰？(3)Cdh 1-APC的哪些神经元靶点控制哺乳动物大脑中的模式？我们将以啮齿类动物脑为模型系统，应用细胞和分子生物学、生物化学技术、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.