Our research focuses on understanding the molecular mechanisms underlying neural circuit formation during development and regeneration following injury. Our lab uses a free-living tiny roundworm, called Caenorhabditis elegans, as a model. The defined cell lineage, completely mapped connectome and rapid life cycle of this organism greatly facilitate investigating nervous system at the subcellular resolution. Combining classic genetic analysis with laser microsurgery, in vivo live imaging technique and molecular and cellular manipulations, we are discovering conserved mechanisms playing key roles in neural circuit formation, axon regeneration and degeneration. Our ultimate goal is to connect the studies of basic mechanisms to the understanding of human brain development, disorders and repair.
Our current research is focused on three topics.
Using the Development of RME Neurons as a Model to Study Neural Circuit Formation. The development of RME neural circuit resembles some critical steps of mammalian cortex development, such as neuronal migration, layer formation, axon/dendrite differentiation and synapse specification. Four RME neurons are generated at the surface of embryo, and then migrate toward the center of embryo. After arriving at the pharynx region, RME left and right neurons adjust their positions to align four RME neurons with the same distance. RME neurons also undergo axon/dendrite development and synapse formation to build the connections between neurons. During this process, transient synapses are formed at the end of dorsal/ ventral neurites and are eliminated during neuron maturation. Using the development of RME neurons as a model, we conducted a forward genetic screen and isolated 14 mutants affecting different stage of neural circuit formation. Through further analysis of these mutants we are uncovering novel mechanisms regulating neuronal migration, axon/dendrite differentiation and synapse elimination.
Identifying and Characterizing New Regulators of the DLK-1 Pathway. The conserved DLK pathway is essential for axon regeneration. Genetic studies in C. elegans place DLK-1 at the center of axon regeneration signaling network. We have identified several novel genes involving in regulation of cytoskeleton dynamic and vesicular trafficking and acting downstream of DLK. Given the important roles of DLK pathway, studies of their regulatory mechanisms will advance our knowledge of neural diseases and provide new targets for clinical research.
Investigating Axon Degeneration. After axonal injury, the proximal axon initiates regeneration, while the distal segment undergoes degeneration called Wallerian degeneration. In mice, suppression of Wallerian degeneration often induces the decrease of axon regeneration, indicating the important role of axon degeneration in regulating regeneration. In many neural diseases including AD, PD, Huntington’s disease and Prion diseases, axon degeneration is observed before loss of neurons, and is considered to be the early step of neurodegeneration. Suppression of axon degeneration could prevent neurodegeneration. Similar to regeneration, axon degeneration is also an active cellular program. However, it remains largely elusive how axons degenerate following injury. We are using a sensitized genetic background to uncover negative and positive regulators of axon degeneration.