Spatial organization of actin polymerizaton during axon guidance.

描述（由申请人提供）：已经鉴定了许多允许神经元生长锥解释和响应细胞外指导线索的细胞内组分，但我们缺乏对这些组分如何在生长锥中建立不对称性的理解。C. elegans提供了一个很好的系统来解决这个问题，因为当神经元对体内的引导信号作出反应时，可以观察到神经元内蛋白质的定位。在C.在线虫中，β-40（也称为DCC）受体变得不对称地定位于细胞最靠近β-6（也称为netrin）引导线索的来源的一侧。这反过来又导致具有生长促进活性的β-10（也称为片状脂质蛋白）的不对称募集，从而导致朝向β-6引导信号源的生长。研究人员认为，β-10的生长促进活性是由肌动蛋白聚合引起的，但β-10与肌动蛋白细胞骨架之间的联系尚不清楚。本提案的目的是确定β-10如何连接到肌动蛋白细胞骨架，导致定向生长促进活动。我们的假设是，β-10（lamellipodin）促进定向生长的不对称招募的WAVE肌动蛋白调节复合物。预计这些研究的结果将使我们能够了解信号复合物如何在空间上组织肌动蛋白调节蛋白，以促进轴突导向线索的响应生长。此外，这些研究的结果可能会有更广泛的意义，因为α-40和α-10已经被牵连在各种各样的其他形态发生事件和新出现的证据表明，不对称定位是他们在这些过程中的作用的关键部分。

DESCRIPTION (provided by applicant): Many of the intracellular components that allow neuronal growth cones to interpret and respond to extracellular guidance cues have been identified, but we lack an understanding of how these components function to establish asymmetry in the growth cone. C. elegans provides an excellent system to address this question, because it is possible to observe the localization of proteins within a neuron as it responds to a guidance cue in vivo. In the HSN neuron of C. elegans, UNC-40 (also known as DCC) receptor becomes asymmetrically localized to the side of the cell closest to the source of the UNC-6 (also known as netrin) guidance cue. This in turn, leads to asymmetric recruitment of MIG-10 (also known as lamellipodin), which has an outgrowth-promoting activity, thereby causing outgrowth towards the source of UNC-6 guidance cue. The outgrowth-promoting activity of MIG-10 is thought to result from actin polymerization, but the link between MIG-10 and the actin cytoskeleton is not understood. The objective of this proposal is to determine how MIG-10 links to the actin cytoskeleton to cause a directional outgrowth-promoting activity. Our hypothesis is that MIG-10 (lamellipodin) promotes directional outgrowth by asymmetrically recruiting the WAVE actin regulatory complex. It is expected that the results from these studies will allow us to build an understanding of how signaling complexes can spatially organize actin regulatory proteins to promote growth in response to axon guidance cues. Furthermore, it is likely that the results of these studies will have broader significance because UNC-40 and MIG-10 have been implicated in a wide variety of other morphogenetic events and emerging evidence suggests that asymmetric localization is a key part of their roles in these processes.