Wnt Signaling in the Mature Central Nervous System

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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.