Neural development in C. elegans
The complexity of synaptic connections in a nervous system is astronomic. In mammalian brain a single neuron can form over 1,000 synaptic connections. These connections can also exhibit dynamic changes throughout lifetime in order to accommodate developmental and environmental demands. For example, learning and memory involve both strengthening of the existing synaptic connections and formation of new synaptic connections. The research in my lab examines the basic processes underlying synapse formation using the nematode C. elegans. The worm is transparent, and its nervous system is simple and accessible. The use of GFP markers allows our analysis to be performed at single-cell and single-synapse in living animals.
How are specific types of neurons generated? We are interested in the molecular program controlling the generation of GABAergic motor neurons. These neurons modulate the locomotion of the worm. We have identified several transcription factors, including the UNC-30 homeodomain protein, the CND-1 HLH protein and the AHR-1 aryl hydrocarbon receptor that control specific aspects of of the GABAergic property of these neurons. We are combining genomic and computational approaches to identify the expression profile for these neurons and to establish the transcriptional network.
How is a neuron guided to their partner? Neurons rely on specialized subcellular structures, called growth cones, to be guided to their targets. Through forward genetic screens, we have identified several max genes (for motor neuron axon guidance). One of the genes, max-1, defines a family of evolutionarily conserved proteins that function to modulate the netrin-signaling pathway.
How does a neuron form synapses with its partners? Synapses are the means that neurons use to communicate with others. At the presynaptic terminal, neurons develop elaborate subcellular structures to facilitate the accumulation and release of synaptic vesicles. Although much of the progress has been made in understanding neurotransmitter release, how the cytoarchitecture of a presynaptic terminal is built is nearly unknown. Using a GFP marker that labels the presynaptic terminals of the GABAergic neurons, we have isolated mutants that display abnormal synaptic morphology. Our analyses of several mutants have identified new signaling molecules that function through GTPases and ubiquitin-mediated protein degration to specify distinct spatial domains at presynaptic terminals.
How do synaptic connections remodel? An intriguing feature of several GABAergic motor neurons is that they remodel their synaptic connections during development. This remodeling is unusual because it involves a complete reversal of information flow without dramatic changes in neuronal morphology. We are particularly interested in exploring this phenomena in the hope that our analysis will shed light on other types of synaptic plasticity that are related to growth, aging, learning and memory. We have found that a nuclear protein LIN-14 controls the timing of the remodeling cell autonomously. Low levels of LIN-14 cause these neurons to remodel early; high levels of LIN-14 delay and prevent remodeling. We are addressing how the regulation of LIN-14 is controlled.
How do nerves regenerate? Understanding how neural circuit forms during normal development has direct implications to the process of how injured neurons recover and regain function in mature animals. We have developed an ultrafast laser-based microsurgery procedure to perform axotomy in C. elegans neurons. The severed axons exhibit robust regrowth within 12-24 hours of surgery. We are characterizing the factors influencing the rate and accuracy of regeneration.
Nakata, K., Abrams, B., Grill, B., Goncharov, A., Huang, X., Chisholm, A. D., and Jin, Y. (2005). Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell 120: 407-420.
Yanik, M. F., Cinar, H., Cinar, H. N., Chisholm, A. D., Jin, Y., and Ben-Yakar, A. (2004). Neurosurgery: functional regeneration after laser axotomy. Nature 432:822.
Huang, X., Powell-Coffman, J. A., and Jin, Y. (2004) The AHR-1 aryl hydrocarbon receptor and its co-factor the AHA-1 aryl hydrocarbon receptor nuclear translocator specify GABAergic neuron cell fate in C. elegans Development 131: 819-828.
Hallam. S. J., Goncharov, A., McEwen, J., Baran, R., and Jin, Y. (2002) The C. elegans SYD-1, a presynaptic protein with PDZ, C2 and rhoGAP domains, specifies axon identity. Nature Neuroscience 5: 1137-1146.
Huang, X., Cheng, H.-J., Tessier-Lavign, M., and Jin, Y. (2002) MAX-1, a novel PH/Myth4/FERM domain cytoplasmic protein implicated in netrin-mediated axon repulsion. Neuron 34: 563-576.
Byrd, D. T., Kawasakki, M., Walcoff, M., Hisamoto, N., Matsumoto, K., and Jin, Y. (2001) UNC-16, a JNK signaling scaffold protein, regulates vesicle transport in C. elegans. Neuron 32: 787-800.
Zhen, M., and Jin, Y. (1999) The liprin protein SYD-2 regulates the differentiation of presynaptic termini in C. elegans. Nature 401:371-375.
Hallam, S. J., and Jin, Y. (1998) lin-14 regulates synaptic remodeling in Caenorhabditis elegans. Nature 395: 78-82 (1998).
Dr. Jin received the B.S. degree from Peking University, China, and the Ph.D. from the University of California, Berkeley. She completed her postdoctoral training at MIT.
|
|
