This proposal focuses on characterizing the molecular mechanisms of axon navigation and connectivity. A normal functioning human nervous system requires the interconnection of billions of neurons. Improper formation or maintenance of these connections leads to neurological abnormalities that result in a number of mental diseases and disorders. How are these connections assembled and integrated? Work over the past twenty years has revealed that the molecular mechanisms of axon guidance and connectivity are well- conserved between simple and complex animals. Simple animals like flies use many of the same guidance signals as mammals. Therefore, as a step towards understanding how complex nervous systems form and properly function, we have pursued a strategy to determine how the simple model fly nervous system is assembled - where we can also apply high-resolution molecular, genetic, biochemical, imaging, and cellular approaches to solving this problem. Indeed, the goal of my research program is to focus on a group of axons within the simple nervous system of the fly embryo and characterize the molecules and mechanisms that guide them to their targets. In particular, elegant studies have now identified a number of the extracellular cues and receptors that guide axons, revealing fundamental mechanisms of how axons form connections. Far less is known, however, of the intracellular signaling pathways and the mechanisms that link these guidance cues and their receptors to the control of axon navigation. As a model, we have been focusing on one of the largest protein families involved in neuronal connectivity, the Semaphorins (Semas). Semas utilize Plexins, large transmembrane proteins found on the axonal surface, as receptors to direct their effects. Yet, how Plexins transduce Sema signals to sculpt connections is still poorly understood. Now, over the past few years, we have had several advances on this front, which have provided new insights into axon guidance and connectivity. We have identified a novel biochemical mechanism (a specific reversible Redox mechanism controlled by Mical and SelR enzymes) that directly regulates the actin cytoskeletal elements necessary for axon guidance and connectivity. We have also uncovered a set of molecular interactors - Sema/Plexins, G proteins, kinases, second messengers, adaptors, and integrin cell adhesion receptors - that directly modulate the ability of an axon to adhere to its substrate. Our observations have led us to hypothesize that axon guidance and connectivity are controlled by both reversible Redox regulation of actin and the modulation of adhesion/de- adhesion. We propose to further test this hypothesis by employing molecular, genetic, biochemical, cell culture, and imaging approaches and the Drosophila model system to follow-up on several lines of preliminary observations that identify 1) new regulatory enzymes that specifically control both the activity and localization of Mical-mediated Redox regulation of actin and 2) new molecular components underlying Sema/Plexin/G- protein-mediated de-adhesion.

Public Health Relevance

Our nervous system controls such remarkable abilities as learning, speaking, and walking only because our neurons communicate in highly organized networks. The goal of this proposal is to characterize the molecular and biochemical mechanisms that enable neurons to find and connect with one another during development and maintain these proper connections through-out adulthood. Understanding how these connections are assembled, integrated, and maintained will suggest solutions to diminish the burden of mental illness, reveal fundamental mechanisms underlying thought, emotion, and behavior, identify therapeutic strategies for multiple brain diseases and disorders, and contribute to healthy recovery following neural trauma.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH085923-09
Application #
9392586
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Panchision, David M
Project Start
2009-04-01
Project End
2019-11-30
Budget Start
2017-12-01
Budget End
2018-11-30
Support Year
9
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Neurosciences
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Yang, Taehong; Terman, Jonathan R (2017) Characterizing PKA-Mediated Phosphorylation of Plexin Using Purified Proteins. Methods Mol Biol 1493:147-159
Alto, Laura Taylor; Terman, Jonathan R (2017) Semaphorins and their Signaling Mechanisms. Methods Mol Biol 1493:1-25
Yoon, Jimok; Kim, Sang Bum; Ahmed, Giasuddin et al. (2017) Amplification of F-Actin Disassembly and Cellular Repulsion by Growth Factor Signaling. Dev Cell 42:117-129.e8
Grintsevich, Elena E; Ge, Peng; Sawaya, Michael R et al. (2017) Catastrophic disassembly of actin filaments via Mical-mediated oxidation. Nat Commun 8:2183
Hung, Ruei-Jiun; Spaeth, Christopher S; Yesilyurt, Hunkar Gizem et al. (2013) SelR reverses Mical-mediated oxidation of actin to regulate F-actin dynamics. Nat Cell Biol 15:1445-54
Yang, Taehong; Terman, Jonathan R (2013) Regulating small G protein signaling to coordinate axon adhesion and repulsion. Small GTPases 4:34-41
Yang, Taehong; Terman, Jonathan R (2012) 14-3-3ýý couples protein kinase A to semaphorin signaling and silences plexin RasGAP-mediated axonal repulsion. Neuron 74:108-21
Hung, Ruei-Jiun; Yazdani, Umar; Yoon, Jimok et al. (2010) Mical links semaphorins to F-actin disassembly. Nature 463:823-7
Williamson, W Ryan; Yang, Taehong; Terman, Jonathan R et al. (2010) Guidance receptor degradation is required for neuronal connectivity in the Drosophila nervous system. PLoS Biol 8:e1000553
He, Huawei; Yang, Taehong; Terman, Jonathan R et al. (2009) Crystal structure of the plexin A3 intracellular region reveals an autoinhibited conformation through active site sequestration. Proc Natl Acad Sci U S A 106:15610-5