Motor circuits often utilize cross-inhibition of opposing muscle groups to achieve alternating body movements. In C. elegans, cross-inhibitory signaling precisely coordinates the contraction and relaxation of body wall muscles, generating the sinusoidal waveform characteristic of nematode movement. The anatomical connections of the motor control circuit have been well characterized. Cholinergic motor neurons form dyadic synapses, simultaneously activating body wall muscle and GABA motor neurons that make inhibitory synaptic connections onto contralateral body wall muscles. However, significant questions remain regarding the molecular mechanisms that coordinate excitatory and inhibitory motor neuron activity. Recently, we isolated six loss-of-function alleles of the nicotinic acetylcholine receptor subunit gene,
acr-12, in a forward genetic screen for modifiers of ACh motor neuron cell death caused by excess nAChR mediated signaling1,2. We found
acr-12 is expressed in both ACh and GABA motor neurons, suggesting
acr-12 receptor complexes may be important for coordinating motor neuron activity. Several pieces of evidence support the notion that
acr-12 serves distinct roles in the two motor neuron classes: (1) ACR-12::GFP fluorescence is concentrated at discrete sites along GABA motor neuron processes, indicating ACR-12 may specifically localize at synapses on these neurons. In contrast, we observe diffuse ACR-12::GFP fluorescence in neuronal processes of ACh motor neurons. (2)
acr-12 loss-of-function mutants are hypersensitive to aldicarb and exhibit distinct locomotory phenotypes that are rescued by cell specific expression of
acr-12 in GABA motor neurons but not ACh motor neurons. (3) Transgenic expression of ACR-12(V/S), a gain-of-function transgene, does not lead to motor neuron death; instead, cell-specific expression in either ACh or GABA motor neurons of
acr-12 mutants leads to opposing phenotypes. ACR-12(V/S) expression solely in ACh motor neurons leads to increased excitatory signaling, resembling what has been previously reported for a gain-of-function
acr-2 allele3. In contrast, GABA neuron-specific expression of ACR-12(V/S) results in reduced locomotory activity. The divergent subcellular localization of ACR-12 across motor neuron classes, as well as the distinct phenotypes of loss-of-function and gain-of-function animals highlight the importance of
acr-12 in the motor circuit. We are now working to precisely define how
acr-12 and other signaling molecules regulate motor neuron activity and coordinate cross-inhibitory signaling in the motor circuit. 1. Barbagallo et al., 2008 C.elegans Neuronal Development Meeting 2. Barbagallo et al. abstract, this meeting 3. Jospin et al. (2010). PloS Biol.