Regulation of Rho by p190 RhoGAPs and the Smurf1 ubiquitin ligase in neurons

在神经元的分化过程中，Rho GTP酶在肌动蛋白细胞骨架响应于内在和外在信号的重塑中发挥重要作用。在成熟神经元的发育中，最引人注目的形态学变化是轴突和树突的形成。在分离的海马神经元的培养物中，最初形成几个长度相似的神经突，它们是等同的，直到其中一个在2DIV时成为轴突并迅速延伸。一天后，剩余的神经突开始生长，分化成树突。树突的延伸可以通过外部因素如轴突导向分子Semaphorin 3A进一步刺激。Rho GTP酶对神经元分化的重要性已被广泛记录。然而，介导Rho的调节以允许神经突在分化期间和响应于细胞外信号的延伸的信号传导途径仅被部分理解。该项目旨在阐明RhoGAP p190和p190-B以及Smurf 1对Rho的泛素化如何决定神经突延伸过程中活性Rho的水平。此外，我们想了解这些途径是如何被细胞外因子如Semaphorin 3A调节的。

During the differentiation of neurons, Rho GTPases play an essential role in the remodelling of the actin cytoskeleton in response to intrinsic and extrinsic signals. The most dramatic morphological change in the development of mature neurons is the formation of axons and dendrites. In cultures of dissociated hippocampal neurons, initially several neurites of similar length are formed that are equivalent until one of them becomes the axon at 2 DIV and extends rapidly. One day later, the remaining neurites begin to grow as they differentiate into dendrites. The extension of dendrites can be stimulated further by extrinsic factors such as the axon guidance molecule Semaphorin 3A. The importance of Rho GTPases for neuronal differentiation has been documented extensively. However, the signalling pathways that mediate the regulation of Rho to allow the extension of neurites during differentiation and in response to extracellular signals are only partially understood. The proposed project intends to elucidate how the RhoGAPs p190 and p190-B together with the ubiquitination of Rho by Smurf1 determine the level of active Rho during the extension of neurites. In addition, we want to understand how these pathways are regulated by extracellular factors like Semaphorin 3A.