The biogenic amines serotonin and octopamine are present in the nematode Caenorhabditis elegans . Serotonin, detected histochemically in whole mounts, is localized in two pharyngeal neurons that appear to be neurosecretory. Octopamine, identified radioenzymatically in crude extracts, probably is also localized in a few neurons. Exogenous serotonin and octopamine elicit specific and opposite behavioral responses in Caenorhabditis elegans , suggesting that these compounds function physiologically as antagonists.
We have isolated 145 fertile mutants of C. elegans that are defective in egg laying and have characterized 59 of them genetically, behaviorally and pharmacologically. These 59 mutants define 40 new genes called egl, for egg-lay ing abnormal. Most of the other mutants are defective in previously identified genes. The egl mutants differ with respect to the severity of their egg-laying defects and the presence of behavioral or morphological pleiotropies. We have defined four distinct categories of mutants based on their responses to the pharmacological agents serotonin and imipramine, which stimulate egg laying by wild-type hermaphrodites. These drugs test the functioning of the vulva, the vulval and uterine muscles and the hermaphrodite-specific neurons (HSNs), which innervate the vulval muscles. Mutants representing 14 egl genes fail to respond to serotonin and to imipramine and are likely to be defective in the functioning of the vulva or the vulval and uterine muscles. Four mutants (representing four different genes) lay eggs in response to serotonin but not to imipramine and appear to be egg-laying defective because of defects in the HSNs; three of these four were selected specifically for these drug responses. Mutants representing seven egl genes lay eggs in response to serotonin and to imipramine. One egl mutant responds to imipramine but not to serotonin. The remaining egl mutants show variable or intermediate responses to the drugs. Two of the HSN-defective mutants, egl-1 and her-1(n695), lack HSN cell bodies and are likely to be expressing the normally male-specific program of HSN cell death. Whereas egl-1 animals appear to be defective specifically in HSN development, her-1(n695) animals exhibit multiple morphological pleiotropies, displaying partial transformation of the sexual phenotype of many cells and tissues. At least two of the egl mutants appear to be defective in the processing of environmental signals that modulate egg laying and may define new components of the neural circuitry that control egg laying.
We isolated two mutants defective in the uptake of exogenous serotonin (5-HT) into the neurosecretory motor neurons of Caenorhabditis elegans. These mutants were hypersensitive to exogenous 5-HT and hyper-responsive in the experiencedependent enhanced slowing response to food modulated by 5-HT. The two allelic mutations defined the gene mod-5 (modulation of locomotion defective), which encodes the only serotonin reuptake transporter (SERT) in C. elegans. The selective serotonin reuptake inhibitor fluoxetine (Prozac) potentiated the enhanced slowing response, and this potentiation required mod-5 function, establishing a 5-HT-and SERT-dependent behavioral effect of fluoxetine in C. elegans. By contrast, other responses of C. elegans to fluoxetine were independent of MOD-5 SERT and 5-HT. Further analysis of the MOD-5-independent behavioral effects of fluoxetine could lead to the identification of novel targets of fluoxetine and could facilitate the development of more specific human pharmaceuticals.Key words: C. elegans; SERT; fluoxetine; serotonin; reuptake; modulation of behavior; SSRI The activity of serotonin (5-HT), a key neuromodulator, is mediated postsynaptically through metabotropic (Martin et al., 1998) and ionotropic (Maricq et al., 1991;Ranganathan et al., 2000) 5-HT receptors and their downstream signaling components (Hille, 1992). 5-HT modulates several behaviors of the nematode Caenorhabditis elegans, including egg laying and locomotion (Horvitz et al., 1982;Trent et al., 1983;Avery and Horvitz, 1990;Schafer and Kenyon, 1995). 5-HT also mediates the enhanced slowing response exhibited by food-deprived nematodes after they encounter bacteria (Sawin et al., 2000). 5-HT neurotransmission can be regulated by the removal of 5-HT from the synaptic cleft by a serotonin reuptake transporter (SERT;Cooper et al., 1996). Na ϩ /Cl Ϫ -dependent SERTs were cloned first from rats (Blakely et al., 1991;Hoffman et al., 1991) and subsequently from other species (Mortensen et al., 1999, and references therein), including humans and Drosophila melanogaster. SERT antagonists, such as the selective serotonin reuptake inhibitors (SSRIs) fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft), are broadly used in the treatment of psychiatric disorders (Schloss and Williams, 1998). Therefore, in addition to the basic question of SERT function and regulation, it is of particular clinical importance to understand SERT function in vivo. SERT-deficient mice do not show gross developmental defects but have reduced 5-HT levels in the brain (Bengel et al., 1998), are insensitive to 3,4-methylenedioxymethamphetamine (ecstasy)-induced hyperactivity (Bengel et al., 1998), and show a brain region-and gender-specific reduction in the density and expression of 5-HT 1a receptors (Li et al., 2000). However, no obvious behavioral defects or abnormal responses to SSRIs in these SERT-deficient mice have been reported.In this article, we report the isolation of two C. elegans SERTdeficient mutants and describe studies of these mutants...
We have characterized two transcripts from the male-determining her-1 locus in Caenorhabditis elegans. The larger transcript, which appears more important for male development, is predicted to encode a novel 175-amino-acid, cysteine-rich polypeptide with an apparent amino-terminal signal sequence and potential cleavage and glycosylation sites. Expression of a full-length cDNA construct for the larger transcript driven by a body-wall-myosin promoter causes extensive masculinization of all sexually dimorphic tissues in XX (normally hermaphrodite) animals. This activity is dependent on the presence of the her-1 signal sequence or a substitute synthetic signal sequence in the encoded polypeptide. These results suggest that a secreted product of the her-1 gene dictates male development. The primary signal for sex determination in Caenorhabditis elegans is the ratio of X chromosomes to autosomes (X/A ratio) (Nigon 1951; Madl and Herman 1979). Genotypes of XO (X/A = 0.5) and XX (X/A = 1.0) normally dictate male and hermaphrodite development, respectively. The two sexes show extensive dimorphism in most tissues: For example, males have a unilobed testis connected to the cloaca and a complex tail specialized for copulation, whereas hermaphrodites, which are selffertile, have a bilobed ovotestis connected to the vulva and a simpler tail (for review, see Hodgkin 1988). Genetic analysis has shown that the primary signal is interpreted through a regulatory cascade (Fig. 1) including seven autosomal genes that control somatic as well as germ-line sex determination (for review, see Hodgkin 1987; Hodgkin 1990) and three X-linked genes that regulate both these genes and the genes that mediate X chromosome dosage compensation (for review, see Villeneuve and Meyer 1990). Although molecular information on some of the corresponding gene products has recently become available (see above reviews and Discussion), the nature of the cascade and its relationship to other known developmental regulatory pathways is not yet clear.The her-1 gene, which is necessary for normal male development in XO animals (Hodgkin 1980), appears to be the point at which the X-linked regulatory genes control sex determination. The activity of her-l, in turn, controls activity of the terminal regulator tra-1 as shown in Figure 1, via tra-2, tra-3, and the fern genes, so that in an XO animal tra-1 function is repressed and male development is permitted. The her-1 gene is defined by 25 loss-of-function (If) mutations; most of these result in complete transformation of XO animals into self-fertile hermaphrodites and have no effect on XX animals (Hodgkin 1980;Trent et al. 1988). Weak If alleles can result in variably transformed intersexual XO animals.Two dominant gain-of-function (gf) mutations at the her-1 locus (n695 and ylO1) result in the opposite phenotype: XX animals are variably transformed (masculinized) into pseudomales (Trent et al. 1983(Trent et al. , 1988(Trent et al. , 1991).This dominant phenotype shows that her-1 expression in XX animals is suffici...
Sexually dimorphic traits in insects are rapidly evolving due to sexual selection which can ultimately lead to speciation. However, our knowledge of the underlying sex-specific molecular mechanisms is still scarce. Here we show that the highly conserved gene, Doublesex (Dsx), regulates rapidly diverging sexually dimorphic traits in the model parasitoid wasp Nasonia vitripennis (Hymenoptera: Pteromalidae). We present here the revised full Dsx gene structure with an alternative first exon, and two additional male NvDsx isoforms, which gives important insights into the evolution of the sex-specific oligomerization domains and C-termini. We show the sex-specific NvDsx expression throughout development, and demonstrate that transient NvDsx silencing in different male developmental stages dramatically shifts the morphology of two sexually dimorphic traits from male to female, with the effect being dependent on the timing of silencing. In addition, transient silencing of NvDsx in early male larvae affects male genitalia tissue growth but not morphology. This indicates that male NvDsx is actively required to suppress female-specific traits and to promote male-specific traits during specific developmental windows. These results also strongly suggest that in N. vitripennis most sex-specific tissues fully differentiate in the embryonic stage and only need the input of NvDsx for growth afterwards. This provides a first insight into the regulatory activity of Dsx in the Hymenoptera and will help to better understand the evolutionary and molecular mechanisms involved in sex-specific development in this parasitoid wasp, which can eventually lead to the development of new synthetic genetics-based tools for biological pest control by parasitoid wasps.Significance StatementIn insects, male and female differentiation is regulated by the highly conserved transcription factor Doublesex (Dsx). The role of Dsx in regulating rapidly evolving sexually dimorphic traits has received less attention, especially in wasps and bees. Here, we mainly focused on Dsx regulation of two sexually dimorphic traits and male genitalia morphology in the parasitoid wasp, Nasonia vitripennis. We demonstrate that Dsx actively regulates male-specific tissue growth and morphology during specific developmental windows. These findings will help to better understand the molecular mechanisms underlying the rapid evolution of sexual differentiation and sexually dimorphic traits in insects, but may also be the starting point for the development of new tools for biological control of pest insects by parasitoid wasps.
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