RESEARCH
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Research HomeMolecular and cellular mechanisms underlying neural development, disorders, and regeneration
PPrecisely-wired neuronal
circuitry underlies the proper and complex functions of the nervous
system. Failures/mistakes in the wiring process often lead to brain
abnormalities associated with cognitive defects and mental illness.We
investigate the molecular and cellular mechanisms underlying a variety of
developmental events that lead to the proper construction of the complex nervous system.
Our unique experimental approaches are based on functional analyses at the
single cell level in combination with sophisticated cellular imaging and
powerful molecular manipulation. The major effort of the laboratory has
been focusing on neuronal motility and signal transduction underlying
neuronal migration, axon growth and guidance, and synaptic plasticity.
These studies will not only provide a mechanistic understanding of these
crucial developmental events, but also allow us to gain substantial
knowledge on the molecular and cellular basis of wiring defects associated
with brain abnormality and mental illness. Importantly, it is our hope
that these basic studies will build the foundation for the development of
potential strategies and treatments to promote regeneration and repair of
damaged neuronal circuitry after neural injuries and degeneration.
Part I: Axonal growth, guidance, and regeneration
Over a century ago, Ramón y Cajal made his landmark observations on the patterns of nerve process outgrowth and connectivity in developing brains and described the motile tip of each elongating axon, the growth cone, as the responsible unit for axon elongation and pathfinding to the target cells. It is well established now that developing axons are guided to their targets by a variety of environmental cues, including long-range diffusible and short-range surface-bound molecules that can either attract or repel the axon. The presence of these guidance cues in temporal and spatial patterns enables the growth cone to navigate through the complex environment of the developing embryo to reach its correct target. As a major focus of the laboratory, we study the signaling pathways and cytoskeletal mechanisms that allow the growth cone to translate extracellular signals to directional movement during guidance. Using state-of-art cellular imaging and manipulation techniques, we have started to elucidate key cellular events that are spatiotemporally restricted to control growth cone extension. Three lines of research are being pursued that target signal transduction at different cellular levels ranging from the plasma membrane to the cytoskeleton. At the membrane level, we study microdomains in spatiotemporal signal transduction of extracellular cues during guidance. At the intracellular level, our efforts are to elucidate intricate signaling cascades (e.g. Ca2+ pathway) that translate extracellular cues to directed axonal growth. Different signaling pathways are likely to interact and eventually converge on the cytoskeleton for directed growth cone movement. The third line of research in the lab investigates the cytoskeletal mechanisms underlying growth cone extension and guidance. We are particularly focusing on the actin cytoskeleton and microtubules, and their coordinated activities and regulation, in growth cone steering and elongation. Furthermore, our recent study shows that spatially regulated synthesis of ß–actin in the growth cone mediates Ca2+-dependent bidirectional turning. These findings, together with studies from other labs, have provided mechanistic insights to a functional role of spatially-regulated synthesis of cytoskeletal proteins in growth cone motility and guidance. In summary, we are actively pursuing these research projects, aiming to elucidate the "missing links" between extracellular cues and directed motility of the nerve growth cone.
p>Inhibitory signaling and axon regeneration: The lack of axon regeneration of the adult central nervous system is in part due to the presence of inhibitory molecules at the injury site, including myelin associated proteins (e.g. MAG and Nogo). Our work on the signaling pathways and cytoskeletal mechanisms in developing axons bears direct implications in axon regeneration after nerve injury. For example, the finding that lipid rafts mediate inhibitory effects of Semaphorin 3A molecules suggests that raft manipulation could be an effective way to combat growth inhibition during nerve regeneration after neural injuries. We are now testing whether membrane raft manipulation can abolish growth inhibition by a number of known axon inhibitory molecules such as MAG, NOGO, and Semaphorins, thus promoting nerve regeneration. Similarly, our work on Ca2+ signaling in growth cone has implicated phosphatases (calcineurin and phosphatase-1) in growth cone repulsion induced by myelin-associated glycoproteins. It is thus plausible that inhibition of these phosphatases could be a potential strategy for overcoming axon inhibition and promoting regeneration. Finally, local protein synthesis could be an additional step in promoting axon regeneration and elongation that can lead to re-wiring of damaged neuronal connections. In summary, we are actively applying our knowledge on signal transduction and cytoskeletal mechanisms learned from developing axons to addressing questions concerning adult axon regeneration.Part II: Axonal transport and neurodegenerative diseases
Alzheimer’s disease (AD) is a progressive neurodegenerative disease highlighted by two pathological hallmarks: extracellular senile plaques containing amyloid ß (Aß) fibrils and intracellular neurofilbrillar tangles consisting of hyperphosphorylated microtubule-associated tau proteins. Recent studies indicate that soluble Aß oligomers exhibit severe inhibition of synaptic functions and plasticity, indicating that these intermediate Aß aggregates, not the fibrils, may be responsible for synaptic deficits in AD brains. We find that soluble Aß molecules can acutely impair fast transport of mitochondria through a specific signaling pathway involving GSK3ß. Our findings are distinct from the long-term toxic effects of Aß on neurons and do not involve cell death. Given that mitochondrial trafficking and localization are essential for many cellular functions including synaptic activities, their inhibition by Aß could play an important role in AD-related dysfunctions of neuronal connectivity. Moreover, transport deficits appear to enhance local APP processing and the production of Aß, therefore Aß impairment of fast transport in general could potentially escalate local Aß production and promote AD pathogenesis. The central hypothesis is that Aß molecules exhibit acute inhibition on neuronal trafficking, which may constitute one of the early Aß adverse effects leading to the disruption of normal neuronal functions and development of AD-related neuronal dysfunctions. We are performing a series of experiments to test this hypothesis. Our work will specifically take advantage of our high-resolution imaging expertise, the manipulability of cultured hippocampal neurons and slices, and our experience in neuronal signal transduction. The goal of this line of studies is to understand the signal transduction mechanisms that link Aß molecules to axonal transport defects and neuronal dysfunctions.
Part III: Other research activities including synapse development and plasticity
In addition to the major programs described above, the lab is also engaging in a wide spectrum of projects that emphasize on the cell biology issues of neural development, degeneration, and regeneration. In particular, we are investigating the cytoskeletal mechanisms that underlie synapse development, plasticity, and dysfunctions. This line of research ranges from the synapse dynamics to the vesicular trafficking of synaptic receptors. The common theme is that the cytoskeleton and its regulation by signaling networks represent the very fundamental basis for dynamic structures and proper functions of nerve cells in the complex brain. Alternations or abnormality in the cytoskeletal structures/dynamics have been shown to underlie many neurological disorders and malfunctions. We believe that this line of basic research will lead to a better understanding of neuronal development and disorders at the molecular and cellular level.
