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Title page for ETD etd-12052011-182146


Type of Document Dissertation
Author Petersen, Sarah Catherine
URN etd-12052011-182146
Title A transcriptional program remodels GABAergic synapses in C. elegans
Degree PhD
Department Cell and Developmental Biology
Advisory Committee
Advisor Name Title
Christopher V. E. Wright Committee Chair
David M. Miller III Committee Member
Donna J. Webb Committee Member
Joshua T. Gamse Committee Member
Keywords
  • transcription
  • C. elegans
  • gene expression
  • plasticity
  • synaptic remodeling
Date of Defense 2011-11-29
Availability unrestricted
Abstract
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.

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.

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.

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