unc-73 is a complex gene that functions in multiple tissue types at different stages of C. elegans development. It is required for normal fertility, pharynx and vulval muscle function and for specific cell migrations. In the nervous system
unc-73 also plays a role in axon guidance and neurotransmission (Steven et al, 1998; Steven et al, 2005).
unc-73 encodes at least eight protein isoforms that are differentially expressed. These isoforms are thought to function primarily through the activity of their respective RhoGEF domains, which catalyze the activation of members of either the Rac or Rho GTPase subfamilies. Here we attempt to better define the role of the UNC-73 isoforms in neurotransmission. Isoform specific rescue experiments previously revealed that the RhoGEF-2 domain-containing UNC-73C1, C2/F and E isoforms act redundantly to regulate the speed of locomotion. Transgenic animals lacking these isoforms have a lethargic movement phenotype that can be rescued by the expression of any individual isoform from this group. By using different cell-specific or inducible promoters to drive the expression of UNC-73E in transgenic
unc-73 mutant animals we have begun to identify the temporal and spatial requirements of UNC-73E function. We have found that UNC-73E acts within the nervous system to physiologically regulate locomotion. It was recently reported that UNC-73E is an effector of Galphaq (Williams et al, 2007), however, it is still not clear how the UNC-73 isoforms function with Rho to regulate neurotransmission. In our hands the lethargic
unc-73 mutants are not aldicarb resistant, which suggests that the UNC-73 RhoGEF-2 isoforms do not have an obvious defect in acetylcholine neurotransmitter release. This is consistent with the observation that restricted expression of UNC-73E in the cholinergic motor neurons does not rescue the
unc-73lethargic movement phenotype. Epistasis analysis has revealed that activating mutations in different components of the Galphas pathway rescue the
unc-73 lethargic movement phenotype caused by the loss of the UNC-73C1, C2/F and E isoforms. We are examining the possibility that these UNC-73 isoforms are required for the production or release of a neuromodulator that functions upstream of a Galphas-coupled receptor.