deg-3 is a subunit of a nicotinic AChR that can mutate to cause neuronal degeneration, a process typified by extensive cell swelling followed by cell death (Treinin and Chalfie, (1995). Neuron 14: 871-877). Studies of
deg-3 induced cell degeneration and the morphologically similar degenerin induced degenerations, suggested a model linking channel hyperactivity to cell death. This model suggests that cell swelling is the result of increased ion influx to the cell, and the concomitant osmotic imbalance. In order to characterize the
deg-3 dependent degeneration process we have screened for suppressors of this process. This screen led to the identification of 8 genes (11 mutations), suggesting a complex network of genes interacting in the degeneration process. Initial characterization of these mutations includes analyzing their effect on the degeneration process, as measured by the number of swollen cells, and by the number of surviving cells. This analysis shows that these mutations belong to two groups: 1. Supppressors which have no effect on cell swelling but do result in increased cell survival. The existence of this type of suppressors suggests that cell swelling does not lead directly to cell death. 2. Suppressors which have a strong suppressing effect on both cell swelling and cell death. This suppression of cell swelling (seen in mutations affecting
des-2 and
des-5), suggests a reduction in mutant DEG-3 channel activity. Indeed,
des-2 codes for a nAChR subunit (formerly named
deg-3b, or
acr-4) which is part of the
deg-3 operon. Expression of this gene and
deg-3 in an heterologous expression system, Xenopus oocytes, shows that both are needed for channel formation (Gillo, et al. International Worm Meeting 1997, p.109). Thus
des-2 codes for a subunit of the DEG-3 channel.
des-5, the second gene of this group, appears to play a role in regulating the activity of many C. elegans nAChRs, as mutations in this gene also lead to levamisole resistance, and reduced pharyngeal pumping.