The Wingless Transduction Pathway in Synapse Development

本项目的目标是了解发育和发育过程中跨突触交流的机制。 突触的可塑性。在过去的许多年里，在这笔赠款的支持下，我们与 对我们理解突触可塑性信号的基本含义，展示了WNTS的重要作用 在这些过程中。WNTS与严重的神经疾病之间的联系，如阿尔茨海默病，以及 精神分裂症1，2，这使得我们的发现特别有影响力。在过去的5年里，由 这一优异奖使我们能够显著扩大我们的专业领域，这导致了几个高度 重大和意想不到的发现，这些发现构成了该奖项未来5年拟议工作的基础。 特别是，我们记录了一种全新的细胞间通信模式，ViSyToR(病毒突触转移 RNA)是一种类似逆转录病毒的跨细胞信使核糖核酸转移机制。此外，我们提供了令人信服的证据 ViSyToR被用来携带编码突触可塑性的主要调节因子Arc/Arg2.1的mRNA。在 我们将(A)检验Copia反转录转座子形式具有 在跨突触交流中的生理作用，(B)确定其他GAG编码基因和转座子 通过ViSyToR途径在跨突触交流中的作用，以及(C)揭示ViSyToR的机制 突触的功能，包括Wg和dArc1之间的相互作用。

The goal of this project is to understand mechanisms of trans-synaptic communication during development and plasticity of synapses. During the past many years, with support from this grant, we have pioneered work with fundamental implications to our understanding of synaptic plasticity signals, demonstrating an essential role for Wnts in these processes. The linkage between Wnts and severe neurological conditions, such as Alzheimer’s disease, and schizophrenia1,2, makes our findings particularly impactful. During the past 5 years, the funding stability provided by this MERIT award, enabled us to significantly expand our field of expertise, which resulted in several highly significant and unexpected discoveries, which form the basis of the work proposed over the next 5 years of the award. In particular, we documented a totally novel mode of intercellular communication, ViSyToR (Viral Synaptic Transfer of RNA) a retroviral-like mechanism of trans-cellular mRNA transfer. In addition, we provided compelling evidence that ViSyToR was used to carry mRNA encoding a master regulator of synaptic plasticity, Arc/Arg2.1. In the proposed extension of this MERIT award we will (a) test the hypothesis that Copia retrotransposon forms have a physiological role in trans-synaptic communication, (b) determine if other Gag-encoding genes and transposons function in trans-synaptic communication using the ViSyToR pathway, and (c) unravel mechanisms of ViSyToR function at synapses, including interactions between Wg and dArc1.