NORMAL GENOMIC

• Kullyev A et al.
• A genetic survey of fluoxetine action on synaptic transmission inCaenorhabditis elegans.
• Genetics. 2010; 186: 929-41
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• Fluoxetine is one of the most commonly prescribed medications for manybehavioral and neurological disorders. Fluoxetine acts primarily as aninhibitor of the serotonin reuptake transporter (SERT) to block theremoval of serotonin from the synaptic cleft, thereby enhancing serotoninsignals. While the effects of fluoxetine on behavior are firmlyestablished, debate is ongoing whether inhibition of serotonin reuptake isa sufficient explanation for its therapeutic action. Here, we provideevidence of two additional aspects of fluoxetine action through geneticanalyses in Caenorhabditis elegans. We show that fluoxetine treatment andnull mutation in the sole SERT gene mod-5 eliminate serotonin in specificneurons. These neurons do not synthesize serotonin but importextracellular serotonin via MOD-5/SERT. Furthermore, we show thatfluoxetine acts independently of MOD-5/SERT to regulate discreteproperties of acetylcholine (Ach), gamma-aminobutyric acid (GABA), andglutamate neurotransmission in the locomotory circuit. We identified thattwo G-protein-coupled 5-HT receptors, SER-7 and SER-5, antagonisticallyregulate the effects of fluoxetine and that fluoxetine binds to SER-7.Epistatic analyses suggest that SER-7 and SER-5 act upstream of AMPAreceptor GLR-1 signaling. Our work provides genetic evidence thatfluoxetine may influence neuronal functions and behavior by directlytargeting serotonin receptors.

• Kemp BJ, Church DL, Hatzold J, Conradt B, Lambie EJ
• Gem-1 encodes an SLC16 monocarboxylate transporter-related protein thatfunctions in parallel to the gon-2 TRPM channel during gonad developmentin Caenorhabditis elegans.
• Genetics. 2009; 181: 581-91
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• The gon-2 gene of Caenorhabditis elegans encodes a TRPM cation channelrequired for gonadal cell divisions. In this article, we demonstrate thatthe gonadogenesis defects of gon-2 loss-of-function mutants (including anull allele) can be suppressed by gain-of-function mutations in the gem-1(gon-2 extragenic modifier) locus. gem-1 encodes a multipass transmembraneprotein that is similar to SLC16 family monocarboxylate transporters.Inactivation of gem-1 enhances the gonadogenesis defects of gon-2hypomorphic mutations, suggesting that these two genes probably act inparallel to promote gonadal cell divisions. GEM-1GFP is expressed withinthe gonadal precursor cells and localizes to the plasma membrane.Therefore, we propose that GEM-1 acts in parallel to the GON-2 channel topromote cation uptake within the developing gonad.

• de la Cruz IP, Levin JZ, Cummins C, Anderson P, Horvitz HR
• sup-9, sup-10, and unc-93 may encode components of a two-pore K+ channelthat coordinates muscle contraction in Caenorhabditis elegans.
• J Neurosci. 2003; 23: 9133-45
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• Genetic studies of sup-9, unc-93, and sup-10 strongly suggest that thesegenes encode components of a multi-subunit protein complex thatcoordinates muscle contraction in Caenorhabditis elegans. We cloned sup-9and sup-10 and found that they encode a two-pore K+ channel and a noveltransmembrane protein, respectively. We also found that UNC-93 and SUP-10colocalize with SUP-9 within muscle cells, and that UNC-93 is a member ofa novel multigene family that is conserved among C. elegans, Drosophila,and humans. Our results indicate that SUP-9 and perhaps other two-pore K+channels function as multiprotein complexes, and that UNC-93 and SUP-10likely define new classes of ion channel regulatory proteins.

• Hobert O, Ruvkun G
• Pax genes in Caenorhabditis elegans: a new twist.
• Trends Genet. 1999; 15: 214-6

• Lim HH, Park BJ, Choi HS, Park CS, Eom SH, Ahnn J
• Identification and characterization of a putative C. elegans potassiumchannel gene (Ce-slo-2) distantly related to Ca(2+)-activated K(+)channels.
• Gene. 1999; 240: 35-43
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• Two putative homologues of large conductance Ca(2+)-activated K(+) channelalpha-subunit gene (slowpoke or slo) were revealed by C. elegans genomesequencing. One of the two genes, F08B12.3 (Ce-slo-2), shows a relativelylow amino acid sequence similarity to other Slo sequences and lacks keyfunctional motifs, which are important for calcium and voltage sensing.However, its overall structure and regions of homology, which areconserved in all Slo proteins, suggest that Ce-SLO-2 should belong to theSlo channel family. We have cloned a full-length cDNA of the Ce-slo-2,which encodes a protein containing six putative transmembrane segmentswith a K(+)-selective pore and a large C-terminal cytosolic domain. Greenfluorescent protein (GFP) and whole-mount immunostaining analyses revealedthat Ce-slo-2 is specifically expressed in neuronal cells at the nervering, at the ventral nerve cord of the mid-body, and at the tail region.We have also identified a putative human counterpart of Ce-slo-2 from ahuman brain EST database, which shows a stretch of highly conserved aminoacid residues. Northern blot and mRNA dot blot analyses revealed a strongand specific expression in brain and skeletal muscle. Taken together, ourdata suggest that Ce-slo-2 may constitute an evolutionarily conserved geneencoding a potassium channel that has specific functions in neuronalcells.

• Sym M, Robinson N, Kenyon C
• MIG-13 positions migrating cells along the anteroposterior body axis of C.elegans.
• Cell. 1999; 98: 25-36
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• The C. elegans Q neuroblasts and their descendants migrate along theanteroposterior (A/P) body axis to positions that are not associated withany obvious landmarks. We find that a novel protein, MIG-13, is requiredto position these cells correctly. MIG-13 is a transmembrane protein whoseexpression is restricted to the anterior and central body regions by Hoxgene activity. MIG-13 functions non-cell autonomously within these regionsto promote migration toward the anterior: loss of mig-13 activity shiftsthe Q descendants toward the posterior, whereas increasing the level ofMIG-13 shifts them anteriorly in a dose-dependent manner. Our findingssuggest that MIG-13 is a component of a global A/P migration system, andthat the level of MIG-13 determines where along the body axis thesemigrating cells stop.