The Frizzled Nuclear Import Pathway in Synapse Development

描述（由申请人提供）：本项目的目标是阐明在突触发育和活动依赖可塑性过程中受调控的遗传程序。核功能研究的最新进展揭示了协调基因表达的核亚结构域组织中前所未有的动态变化。然而，调节这些动态的生理途径在很大程度上是未知的。我们已经确定了一个关键的转导级联，涉及Wnt家族成员及其受体，在活动依赖性突触生长期间突触和细胞核之间的通信。在哺乳动物大脑中，Wnt在突触发育和可塑性中的重要作用也已被发现，许多认知障碍，如精神分裂症、双相情感障碍和阿尔茨海默病均显示Wnt信号的改变。因此，了解wnt如何在大脑中发挥作用是一个具有重要临床意义的高度重要的领域。我们的研究表明，突触中的Wnt信号激活了一种新的信号通路，即卷曲核输入（FNI）通路，在该通路中，Wg受体DFrizzled2 （DFz2）片段被输入细胞核。在细胞核内，这个DFz2片段与a型层蛋白lamin - c一起建立了一个专门的亚结构域，通过控制mRNA的生物发生来调节基因表达。重要的是，a型纤层蛋白的改变与一组遗传性疾病有关，即纤层病，它对神经肌肉系统的功能具有毁灭性的影响。在这个项目中，我们建议研究这个核亚域在活动依赖的突触可塑性中的功能。特别是，我们建议(1)确定核亚结构域在控制核mRNA聚腺苷化中的作用，并确定受该途径调节的基因，(2)确定运动神经元刺激期间核亚结构域的动力学，以及(3)开始表征受该转导级联调节的重要基因。我们预测这些研究将对我们理解突触事件如何传递到细胞核以调节基因表达具有重要意义。最终，我们期望所提出的研究将与我们对与Wnt信号功能障碍相关的认知障碍的理解高度相关，并确定在层状病变中改变的细胞事件。

DESCRIPTION (provided by applicant): The goal of this project is to elucidate the genetic programs that are regulated during synaptic development and activity-dependent plasticity. Recent advances in the study of nuclear functions reveal an unprecedented dynamics in the organization of nuclear subdomains which coordinate gene expression. However, the physiological pathways that regulate these dynamics are largely unknown. We have identified a critical transduction cascade, involving a member of the Wnt family and its receptor, in the communication between the synapse and the nucleus during activity-dependent synaptic growth. Essential roles of Wnts in synapse development and plasticity have also been uncovered in the mammalian brain, and a number of cognitive disorders, such as schizophrenia, bipolar disorder, and Alzheimer's disease show alterations in Wnt signaling. Thus, understanding how Wnts function in the brain is a highly significant area with important clinical implications. Our studies demonstrate that Wnt signaling at synapses activates a novel signaling pathway, the Frizzled Nuclear Import (FNI) pathway, in which a fragment of the Wg receptor, DFrizzled2 (DFz2), is imported into the nucleus. Within the nucleus, this DFz2 fragment, together with the A-type lamin, Lamin-C, establishes a specialized subdomain, which regulates gene expression by controlling mRNA biogenesis. Importantly, alterations in A-type lamins have been involved in a group of hereditary disorders, the laminopathies, which have devastating impact on the function of the neuromuscular system. In this project we propose to investigate the function of this nuclear subdomain in activity-dependent synaptic plasticity. In particular, we propose to (1) determine the role of the nuclear subdomain in controlling nuclear mRNA polyadenylation and to identify the genes that are regulated by this pathway, (2) determine the dynamics of the nuclear subdomain during motorneuron stimulation, and (3) begin the characterization of an important gene regulated by this transduction cascade. We predict that these studies will be highly significant for our understanding of how synaptic events are communicated to the nucleus to regulate gene expression. Ultimately, we expect that the proposed studies will be highly relevant to our understanding of cognitive disorders associated with the malfunction of Wnt signaling and to identify the cellular events that are altered in laminopathies.