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Molecular mechanisms of neuronal morphogenesis during development and regeneration

The overall goal of our research is to understand the molecular mechanisms underlying development of the mammalian nervous system. Specifically, we are interested in understanding how neurons generate their complex morphology and form proper circuitries during development and how neurons regenerate to restore connections after brain or spinal cord injuries.

1. GSK3 signaling in neural development

Changes in glycogen synthase kinase 3 (GSK3) activity have been associated with many psychiatric and neurodegenerative diseases, including Alzheimer’s disease, schizophrenia, and autism spectrum disorders. Many of the genes associated with these disorders encode proteins involved in GSK3 signaling, such as Disrupted-In-Schizophrenia 1 (DISC1), Neuregulin 1, PTEN, serotonin, tuberous sclerosis complex 1/2 (TSC1/2), and adenomatous polyposis coli (APC). Recent evidence suggests that GSK3s and their upstream and downstream regulators have key roles in many fundamental processes during neural development, including neurogenesis, neuronal polarization, and axon outgrowth. Therefore, a better understanding of the role of GSK3 in brain development could provide insight into the etiology of these disorders and possibly open up the potential of a new library of therapeutic targets. We are using cutting edge technologies, such as biosensor, protein chips, and high resolution live cell imaging, to dissect how GSK3 activity is regulated in neurons and how GSK3 signaling controls neural development.

2. Promoting axon regeneration after spinal cord or brain injuries

The failure of axon regeneration in the mammalian CNS is due to reduced ability of adult CNS neurons to support axon growth, as well as the hostile environment of adult CNS contributed by inhibitory molecules, such as myelin based inhibitors and inhibitory chondroitin sulfate proteoglycans (CSPGs). Therefore, one goal of this project is to identify signaling pathways that underlie the intrinsic axon regeneration ability of adult PNS neurons, which regenerate robustly after peripheral nerve injuries. We will then test if such pathway can be harnessed by adult CNS neurons to boost their regeneration competence. Another goal of the project is to manipulate the nerve growth cone, which is not only the machinery that drives axon growth but also the final target of inhibitory molecules, and determine if it can promote axon regeneration in an inhibitory environment. Several neural injury models in the spinal cord or the peripheral nerves are used in this project.

3. Epigenetic regulation of neuronal morphogenesis during development and regeneration

            Regulation of gene expression is important for almost every biological process, including neuronal morphogenesis, such as neuronal migration and axon/dendrite growth during development and axon regeneration after injuries. Epigenetic regulation independent of changes in DNA sequences is emerging to be a key cellular mechanism to control gene expression. There are three major epigenetic modifications, including DNA methylation, histone modification, and non-conding RNAs. In this project we will explore the roles of histone modification and microRNAs in regulation of neuronal morphogenesis during development or regeneration.

4. Live cell imaging of signal transduction and cytoskeletal reorganization in neurons

We are interested in understanding how extracellular signals are tranduced inside the neurons to control neuronal migration, axon growth and axon guidance. As signal transduction in cells is highly spatial and temporal regulated, the best way to study is to visualize it directly in live cells using biosensors. Therefore, in this project we will perform live cell imaging of signal transduction during development and regeneration using several available biosensors. We will also use state of art imaging techniques, such as TIRF, to achieve high-resolution imaging of cytoskeletal dynamics in nerve growth cones during growth cone migration and steering. In addition to dissociated neurons, we are interested in imaging axon regeneration in live adult mice after peripheral or spinal cord injuries.