Wnt Signaling in the Mature Central Nervous System

神经元之间突触连接之间的信息传递是大脑功能(如感知、动作和认知)的基础，突触交流强度的变化被广泛认为是学习和记忆的基础。WNT信号是一组高度保守的生化信号转导通路，参与多种胚胎发育过程。Wnt信号元件在成熟的大脑中的存在表明，Wnt信号也可能在成人的大脑功能调节中发挥作用。本项目研究了Wnt信号在成熟大脑中的作用和作用机制，从Wnt启动信号转导的受体到转导过程的靶点，如参与突触通讯和可塑性的关键蛋白质。这些发现提供了对参与胚胎发育的信号通路如何重新部署以在成年生物体中实现持久修改的洞察。它们还为突触传递受损情况下的治疗方法的发展提供了信息。此外，该项目为来自代表性不足群体的学生和博士后研究人员提供培训机会，目的是增加他们对科学专业的参与。WNT信号是一种高度保守的信号转导机制，调节后生动物的胚胎发育；然而，WNT信号成分在脊椎动物成熟的中枢神经系统(CNS)中的持续表达表明，WNT信号级联可能在胚胎发育以外的脑功能调节中发挥作用。研究人员最近的发现表明，非规范的Wnt配体上调由NMDA型谷氨酸受体介导的突触电流。这种调节需要Wnt受体ROR2，细胞内钙离子的增加，以及PKC和JNK的激活。本项目的目标是：(1)确定Wnt受体ROR2是如何被激活的，以及它是否足以启动导致谷氨酸能突触传递调节的信号级联反应，以及(2)解开由ROR2受体激活而触发的信号级联反应。为了实现这些目标，人们应用了一系列的方法，包括生化技术、实时荧光Förster共振能量转移(FRET)，在一些实验中结合FRET生物传感器、钙成像和电生理学。了解脊椎动物成熟中枢神经系统中的ROR2信号有助于洞察Wnt信号的一般情况，有助于更好地理解突触可塑性的调节，并最终为一个一般过程提供原则证明证据，通过这个过程，生物体生命早期使用的生物机制可以被用于体内平衡过程或新的生物功能。该项目由综合有机体系统部门的神经系统集群的调制计划、分子和细胞生物科学部门的细胞动力学和功能集群以及新兴前沿部门的生命风险基金规则共同资助。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

Information transmission across synaptic connections between neurons is fundamental to brain functions, such as perception, action, and cognition, and changes in the strength of synaptic communication is widely believed to underlie learning and memory. Wnt signaling is a group of highly conserved biochemical signal transduction pathways known for their involvement in various embryonic processes. The presence of Wnt signaling elements in the mature brain suggests that Wnt signaling may also play a role in the regulation of brain functions in the adult. This project examines the role and mechanisms of action of Wnt signaling in the mature brain, from the receptors through which Wnt initiates signal transduction to the targets of the transduction process, such as proteins critically involved in synaptic communication and plasticity. The findings provide insights into how signaling pathways involved in embryonic development are re-deployed to effect lasting modifications in adult organisms. They also inform the development of treatments for conditions in which synaptic transmission is compromised. In addition, the project provides training opportunities for students and postdoctoral researchers from underrepresented groups, with the goal of increasing their participation in science professions.Wnt signaling is a highly conserved signal transduction mechanism that regulates embryonic development of metazoans; however, the sustained expression of Wnt signaling components in the mature central nervous system (CNS) of vertebrates suggests that Wnt signaling cascades might also play a part in regulating brain function beyond embryonic development. Recent findings by the investigator indicate that a non-canonical Wnt ligand upregulates synaptic currents mediated by NMDA-type glutamate receptors. This regulation requires Wnt receptor RoR2, an increase in intracellular Ca2+, and activation of PKC and JNK. The objectives of this project are to: (1) determine how the Wnt receptor RoR2 is activated and whether it is sufficient to initiate the signaling cascade leading to regulation of glutamatergic synaptic transmission, and (2) unravel the signaling cascade triggered by activation of RoR2 receptors. To achieve these objectives, a range of approaches are applied, including biochemical techniques, live fluorescence Förster resonance energy transfer (FRET), in some experiments combined with FRET based biosensors, Ca2+ imaging, and electrophysiology. Understanding how RoR2 signals in the mature CNS of vertebrates provides insight into Wnt signaling in general, contributes to better understanding of the regulation of synaptic plasticity, and ultimately offers proof-of-principle evidence for a general process by which biological mechanisms used early in an organism's life can be coopted in the mature organism for homeostatic processes or new biological functions. This project was co-funded by the Modulation Program in the Neural Systems Cluster in the Division of Integrative Organismal Systems, the Cellular Dynamics and Function Cluster in the Division of Molecular and Cellular Biosciences, and the Rules of Life Venture Fund in the Division of Emerging Frontiers.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.