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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 neuronal circuits are highly conserved between C. elegans and humans. We use AVM axon guidance as a model system to understand neuronal connectivity. The molecules that guide the AVM axons toward the ventral midline in C. elegans are similar to those that direct commissural neurons toward the floor plate in human spinal cords. Thus, what we learn in C. elegans will likely be relevant to the development and regeneration of the human nervous system.
During development of the nervous system, the C. elegans anterior ventral microtubule axon (AVM) is guided to the ventral nerve cord by two cues, the ventral UNC-6 / netrin attractant recognized by the UNC-40 / DCC receptor and the dorsal SLT-1 / slit repellent recognized by the SAX-3 / Robo receptor. 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 intermediate targets, but upon arriving they must switch their responsiveness to guidance cues at the intermediate targets such that they are no longer sensitive to these cues but rather can move away. Thus, commissural axons in Drosophila and vertebrates and AVM axons in C. elegans are less responsive to unc-6 / netrin as they grow to the intermediate targets at the ventral nerve cord. 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 the intermediate target. Our lab is using a genetic and optical approach to identify molecular mechanisms that inhibit netrin attraction.
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 axon regeneration enables us to identify several regeneration patterns that are conserved between C. elegans and vertebrates. For example, we observe 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 axon growth ability with aging, but it is not known why. Many of the positive regulators of axon growth have been identified and well studied. Our major goal is to test a related hypothesis: that there are also negative regulators of axon growth that limit the brain’s ability to grow out axon. 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 treatment of neurodegenerative diseases of aging by harnessing hidden neuronal ability to reorganize itself.
We are also interested in understanding how engulfment cells help clean up neuronal “waste”. In mammals, flies, and worms, when a neuron’s connection (axon) is injured, it degenerates and sheds debris. When that happens, engulfment cells move in the injury site and remove these wastes. We want to understand why it is important to remove axon debris and to identify the mechanisms that allow engulfment cells to sense debris and engulf them. Axon debris can also be generated during axon pruning, which is a process widely used for the refinement of the neuronal circuit assembly. We are investigating whether similar mechanisms are used for removal of these early neuronal wastes.
We collaborate with Dr. Chiou-Fen Chuang's lab in studying developmental mechanisms that establish stochastic neuronal diversity in C. elegans.
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