The function of the nervous system is defined by specific patterns of connections between neurons. The molecular determinants of synaptic specificity are largely unknown, however. In the nematode, C. elegans, UNC-4 (homeodomain transcription factor) and its co-repressor, UNC- 37/Groucho, function to ensure that VA motor neurons synapse with the appropriate interneuron partners, unc-4 and unc-37 mutants display a movement defect due to the miswiring of VA motor neurons with inputs from interneurons normally reserved for their lineal sister cells, the VB motor neurons. We propose that UNC-4/UNC-37 preserve normal inputs to VA motor neurons by repressing B motor neuron-specific genes that induce B-type synaptic inputs. The goal of this project is to identify these UNC-4 target genes and to establish their mode of action. FACS will be used to isolate motor neurons expressing A-type or B-type GFP markers from wildtype, unc-4 and unc-37 backgrounds. Labeled mRNA from these cells will be used to interrogate the Affymetrix C. elegans microarray. Authentic unc-4 regulated genes should be normally expressed in Btype motor neurons and upregulated in A-type motor neurons in unc-4 and unc-37 mutants. Transgenic animals expressing GFP reporter genes will be constructed to assess in vivo expression and unc-4 and unc-37 regulation. Presumptive unc-4 target genes will be genetically ablated and potential changes in synaptic connectivity examined by high resolution microscopy. The conservation of UNC-4 and UNC-37 expression in the vertebrate spinal cord suggests that the target genes this study reveals may also regulate synaptic choice in more complex nervous systems.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31NS046923-01
Application #
6691766
Study Section
Special Emphasis Panel (ZRG1-F03A (20))
Program Officer
Leblanc, Gabrielle G
Project Start
2004-03-01
Project End
2007-02-28
Budget Start
2004-03-01
Budget End
2005-02-28
Support Year
1
Fiscal Year
2004
Total Cost
$28,142
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Touroutine, Denis; Fox, Rebecca M; Von Stetina, Stephen E et al. (2005) acr-16 encodes an essential subunit of the levamisole-resistant nicotinic receptor at the Caenorhabditis elegans neuromuscular junction. J Biol Chem 280:27013-21
Fox, Rebecca M; Von Stetina, Stephen E; Barlow, Susan J et al. (2005) A gene expression fingerprint of C. elegans embryonic motor neurons. BMC Genomics 6:42