Neurons adopt polarized morphologies to direct information flow in the nervous system. The assembly of distinct presynaptic and postsynaptic regions is necessary for the transmission of signals from one neuron to the next. These domains may be remodeled by developmental events that alter both axonal and dendritic compartments. The capacity of neurons to remodel polarity is evolutionarily conserved but the mechanisms that govern this process are largely unknown. The GABAergic motor neurons in the nematode C. elegans display a striking example of developmentally regulated synaptic remodeling. Dorsal D (DD) motor neurons initially innervate ventral muscles but switch polarity after hatching to synapse with dorsal muscle. Ventral D (VD) motor neurons that arise during this period are prevented from remodeling by UNC-55, a member of the conserved family of COUP transcription factors. The goal of this project is to exploit this model system to identify molecular factors that govern motor neuron remodeling.
In Aim 1, I will test the hypothesis that a novel mechanism, independent of known synaptogenic proteins SYD-1 and SAD-1, drives DD motor neuron remodeling and that UNC-55 prevents VD motor neurons from adopting this pathway. To identify the potentially novel determinants of DD rewiring, I have used a powerful cell-specific microarray profiling method to detect ~200 transcripts that regulated by UNC-55 in vivo. In experiments described in Aim 2, I will use specific RNAi-dependent assays to test these candidate genes for roles in DD synaptic remodeling. A pilot screen of selected genes in this data set revealed an independent role for Hedgehog-related genes in synaptic assembly.
Aim 3 is designed to define the mechanism of Hedgehog-related protein function in GABA motor neuron synaptogenesis. In this study, I expect to uncover conserved elements in the mechanism of synaptic remodeling. Thus, these results could lead to significant advances in our understanding of synaptic plasticity and thereby provide a foundation for developing therapeutic approaches for human diseases that disrupt synaptic assembly.
| Miller-Fleming, Tyne W; Petersen, Sarah C; Manning, Laura et al. (2016) The DEG/ENaC cation channel protein UNC-8 drives activity-dependent synapse removal in remodeling GABAergic neurons. Elife 5: |
| Petersen, Sarah C; Watson, Joseph D; Richmond, Janet E et al. (2011) A transcriptional program promotes remodeling of GABAergic synapses in Caenorhabditis elegans. J Neurosci 31:15362-75 |
