Current Projects

Forty percent of genes identified in the human genome have a homolog in C. elegans. Genes that allow neurons to connect with each other to form functional neural circuits are highly conserved between C. elegans and humans. Therefore, study of the C. elegant nervous system is relevant to understanding the human brain. Dr. Chang's lab studies mechanisms regulating neuronal connectivity, regeneration, and degeneration in C. elegans. The molecules that guide neuronal connectivity, regenerate nerves, and regulate neurodegeneration in C. elegans are similar to those that used in human. Thus, what Dr. Chang's lab learns in C. elegans will likely be relevant to the development, regeneration, and degeneration of the human nervous system.

Nerve Pathfinding

During development of the C. elegans nervous system, axons of many neurons, including the anterior ventral microtubule (AVM) axons, are guided to the ventral nerve cord by the UNC-6 (netrin) attractant recognized by its receptor UNC-40 (DCC). Upon reaching the ventral nerve cord, the AVM axon changes its trajectory and moves anteriorly to the nerve ring, a neuropil generally viewed as the animal’s brain. Axons are attracted to targets, but must switch their responsiveness upon arrival so that they are no longer sensitive to guidance cues and can proceed with synapse formation. In Drosophila and vertebrates, netrin signaling is inhibited by slit-induced Robo receptor binding to netrin receptor DCC. However, it is unclear how the netrin signaling is inhibited in C. elegans AVM neurons at targets. Dr. Chang's lab is using a genetic and optical approach to identify molecular mechanisms that inhibit netrin attraction.

Nerve Regeneration

The C. elegans nervous system is composed of 302 neurons with a complete map of all axon trajectories and synaptic connections. The transparency and small size of C. elegans allow us to visualize axonal development and axonal regeneration using time-lapse fluorescent microscopy as well as perform axotomy on any neurons with femtosecond laser ablation in live animals. Femtosecond laser ablation is a new optical scalpel with exquisite precision and reproducibility. The nanometer precision of femtosecond laser ablation, as well as the million-fold shorter exposure interval, allow us to snip individual nerve fibers without collateral damages to the cell body or neighboring fibers.

Using C. elegans as a model organism to study nerve regeneration enables Dr. Chang's lab to identify several regeneration patterns that are conserved between C. elegans and vertebrates. For example, Dr. Chang's lab observes in C. elegans the dichotomy of robust regeneration in the peripheral nervous system versus nonregenerating neurons in the central nervous system. In addition, like vertebrate neurons, C. elegans neurons lose nerve growth ability as they age, but it is not known why. Many of the positive regulators of nerve growth have been identified and well studied. Dr. Chang's major goal is to test a related hypothesis: that there are also negative regulators of nerve growth that limit the brain’s ability to grow out nerves. Are there more of these negative regulators in an aging brain than in the baby’s brain? If such molecules exist, then blocking their function in the aging brain might rejuvenate neurons to a growing state in which neurons can regenerate better. This project has the potential to open a new door for the treatment of neurodegenerative diseases of aging by harnessing the hidden neuronal ability to reorganize itself.

Nerve Degeneration

Dr. Chang's lab is interested in understanding how engulfing cells help clean up neuronal “waste”. In mammals, flies, and worms, when a neuron’s connection is injured, it degenerates and sheds debris. When that happens, engulfing cells move in the injury site and remove these wastes. Dr. Chang wants to understand why it is important to remove nerve debris and to identify the mechanisms that allow engulfing cells to sense debris and engulf them. Nerve debris can also be generated during developmental pruning, which is a process widely used for the refinement of the neural circuit assembly. Dr. Chang's lab is investigating whether similar mechanisms are used for the removal of these early neuronal wastes. Dr. Chang's lab recently establishes new C. elegans models of neuronal senescence and degeneration that display either age-related or early-onset structural and functional decline. Using this new discovery platform, his lab already identified multiple spatial and temporal regulatory mechanisms that regulate the degeneration of neuronal circuits.