Spatial organization of actin polymerizaton during axon guidance.

描述（由申请人提供）：许多允许神经元生长锥解释和响应细胞外引导信号的细胞内成分已经被确定，但我们缺乏对这些成分如何在生长锥中建立不对称性的理解。秀丽隐杆线虫提供了一个很好的系统来解决这个问题，因为它有可能观察到神经元在体内对指导线索作出反应时蛋白质的定位。在秀丽隐杆线虫的HSN神经元中，UNC-40（也称为DCC）受体变得不对称地定位于最靠近UNC-6（也称为netrin）引导信号来源的细胞一侧。这反过来又导致米格-10的不对称招募（也称为lamellipodin），它具有促进生长的活性，从而导致向UNC-6制导信号来源的生长。米格-10的促生长活性被认为是由肌动蛋白聚合引起的，但米格-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米格-10如何与肌动蛋白细胞骨架连接以引起定向生长促进活性。我们的假设是，MIG-10 （lamellipodin）通过不对称招募WAVE肌动蛋白调节复合体来促进定向生长。预计这些研究的结果将使我们能够理解信号复合物如何在空间上组织肌动蛋白调节蛋白，以响应轴突的引导信号促进生长。此外，这些研究的结果很可能具有更广泛的意义，因为UNC-40和米格-10与各种其他形态发生事件有关，新出现的证据表明，不对称定位是它们在这些过程中作用的关键部分。

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. PUBLIC HEALTH RELEVANCE: Normal axon guidance is required for the development of a functional nervous system and genetically encoded disruptions in this process can underlie mental and neurological disorders. Thus, the proposed research will lead to the development of fundamental knowledge that could impact the diagnosis and treatment of these developmental disorders.