Inositol Monophosphatase(IMPase) is a biochemically well-defined, Li+-sensitive enzyme. IMPase is thought to be pivotal in Inositol production and speculated as a therapeutic target of Li+ on bipolar disorder. The in vivo role of IMPase however is largely unknown. From a genetic screen for thermotaxis-defective(ttx) mutants, we isolated an athermotactic mutant
ttx-7(
nj40) which has a missense mutation in F13G3.5. The peptide sequence deduced from the cDNAs showed 45.6% identity with human IMPase. As no other C. elegans genes show such high identity,
ttx-7 seems to encode a sole C. elegans homologue of IMPase. Additionally isolated deletion mutants
ttx-7(
nj50) and
ttx-7(
nj51) showed Ttx defect similar to
nj40, and partial defect in chemotaxis to NaCl.
nj50 that lacks the first exon was regarded a null allele and used mainly. All three mutants showed no gross defect in appearance and reproduction although IMPase is thought to be critical for Inositol production. This indicates that IMPase is in fact dispensable and without it organisms can somehow obtain enough Inositol to live, which is consistent with the studies in yeast and Dictyostelium. Rescuable
ttx-7 genomic fragment tagged with egfp was expressed in a subset of neurons in head, tail, ventral nervecord and several other tissues. Of these,
ttx-7 was expressed in AFD and AWC sensory neurons and their downstream interneuron RIA in the thermotaxis neural circuit. The expression of
ttx-7 cDNA in RIA driven by cell-specific promoters rescued Ttx defect, suggesting that TTX-7 is required in RIA for thermotaxis. This is consistent with genetic epstasis study that genetically activated signal transduction from upstream thermosensory neurons was suppressed by
ttx-7 mutation. As we previously observed the subtle morphological defect in RIA of
ttx-7 mutants, we visualized its synapses with GFP-tagged synaptic proteins. We found that synaptic vesicle protein SNB-1 was mislocalized in
ttx-7, which was rescued by RIA-specific
ttx-7 expression. Surprisingly, exogenous Inositol, but not other sugars, rescued Ttx as well as localization defects. Further, exogenous LiCl caused both defects in N2 worms. These coincidences suggest disruption of synapses may lead to Ttx defect in
ttx-7 mutants. Preliminary results show that both SNB-1 localization and thermotaxis were affected by heatshock-driven
ttx-7 expression and Inositol/LiCl application at adult stage. From these results, we hypothesize that TTX-7/IMPase maintains synapses in adult nervous system by producing Inositol and that Li+, the drug for bipolar disorder, affects behavior by perturbing IMPase. Now we are studying the cell specificity, pharmacology and molecular mechanisms of IMPase function in vivo.