Information flow in nervous systems depends on the asymmetric organization of neurons; neurotransmitters are released from presynaptic domains and stimulate receptors localized to postsynaptic regions. These specialized signaling domains can be reorganized within neurons during development or in response to injury. Although transcription factors are known to regulate synaptic plasticity, downstream genes that contribute to remodeling are largely undefined. To identify these factors, we have studied an example of synaptic remodeling in the nematode Caenorhabditis elegans. In this case, GABAergic Dorsal D (DD) motor neuron synapses are relocated to new sites during larval development. This remodeling program is blocked in Ventral D (VD) GABAergic motor neurons by the COUP nuclear hormone receptor, UNC-55. We exploited this UNC-55 function to identify downstream remodeling genes that encode a diverse array of protein types including ion channels, cytoskeletal components, and transcription factors.
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We show that one of these targets, the Iroquois-like homeodomain protein, IRX-1, functions as a key regulator of synaptic reorganization. IRX-1 is required for remodeling both wild-type DD and unc-55 mutant VD motor neurons, and ectopic IRX-1 expression in VD motor neurons is sufficient to induce remodeling. Our discovery of IRX-1 as an UNC-55-regulated target defines a transcriptional pathway that orchestrates an intricate synaptic remodeling program. The established roles of these conserved transcription factors in mammalian neural development suggest that a similar cascade may also control synaptic plasticity in more complex nervous systems.
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Our study of UNC-55-regulated genes also revealed a role for UNC-8, a degenerin-family acid-sensing ion channel, in synaptic remodeling. Expression of UNC-8 is necessary for execution of the UNC-55-regulated synaptic remodeling program in VD motor neurons. Furthermore, UNC-8 promotes the disassembly of immature ventral synapses during DD remodeling. The potential that UNC-8 channel activity locally destabilizes synapses led us to investigate whether the GABAergic synaptic remodeling program is activity-dependent. We show that both calcium influx and synaptic activity drive remodeling of GABAergic synapses. Thus, we have defined a genetic program that employs both transcriptional and local activity-dependent factors to promote re-organization of synaptic patterning during development.
| Identifer | oai:union.ndltd.org:VANDERBILT/oai:VANDERBILTETD:etd-12052011-182146 |
| Date | 10 December 2011 |
| Creators | Petersen, Sarah Catherine |
| Contributors | Donna J. Webb, Joshua T. Gamse, Christopher V. E. Wright, David M. Miller III |
| Publisher | VANDERBILT |
| Source Sets | Vanderbilt University Theses |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.vanderbilt.edu/available/etd-12052011-182146/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to Vanderbilt University or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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