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The Journal of Neuroscience, March 15, 2001, 21(6):2001-2014

Regulation of Neurotransmitter Vesicles by the Homeodomain Protein UNC-4 and Its Transcriptional Corepressor UNC-37/Groucho in Caenorhabditis elegans Cholinergic Motor Neurons

Kim M. Lickteig¹, Janet S. Duerr², Dennis L. Frisby², David H. Hall³, James B. Rand², and David M. Miller III¹

¹ Department of Cell Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, ² Program in Molecular and Cell Biology, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, and ³ Center for C. elegans Anatomy, Albert Einstein College of Medicine, Bronx, New York 10461

Motor neuron function depends on neurotransmitter release from synaptic vesicles (SVs). Here we show that the UNC-4 homeoprotein and its transcriptional corepressor protein UNC-37 regulate SV protein levels in specific Caenorhabditis elegans motor neurons. UNC-4 is expressed in four classes (DA, VA, VC, and SAB) of cholinergic motor neurons. Antibody staining reveals that five different vesicular proteins (UNC-17, choline acetyltransferase, Synaptotagmin, Synaptobrevin, and RAB-3) are substantially reduced in unc-4 and unc-37 mutants in these cells; nonvesicular neuronal proteins (Syntaxin, UNC-18, and UNC-11) are not affected, however. Ultrastructural analysis of VA motor neurons in the mutant unc-4(e120) confirms that SV number in the presynaptic zone is reduced (~40%) whereas axonal diameter and synaptic morphology are not visibly altered. Because the UNC-4-UNC-37 complex has been shown to mediate transcriptional repression, we propose that these effects are performed via an intermediate gene. Our results are consistent with a model in which this unc-4 target gene ("gene-x") functions at a post-transcriptional level as a negative regulator of SV biogenesis or stability. Experiments with a temperature-sensitive unc-4 mutant show that the adult level of SV proteins strictly depends on unc-4 function during a critical period of motor neuron differentiation. unc-4 activity during this sensitive larval stage is also required for the creation of proper synaptic inputs to VA motor neurons. The temporal correlation of these events may mean that a common unc-4-dependent mechanism controls both the specificity of synaptic inputs as well as the strength of synaptic outputs for these motor neurons.

Key words: synaptic vesicles; cholinergic differentiation; C. elegans; synaptic specificity; neural development; unc-4

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Copyright © 2001 Society for Neuroscience  0270-6474/01/2162001-14$05.00/0

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