Ruvinsky I et al. (2003) Development "Functional tests of enhancer conservation between distantly related species."

Ruvkun G, Ruvinsky I

[Development, 2003]

Expression patterns of orthologous genes are often conserved, even between distantly related organisms, suggesting that once established, developmental programs can be stably maintained over long periods of evolutionary time. Because many orthologous transcription factors are also functionally conserved, one possible model to account for homologous gene expression patterns, is conservation of specific binding sites within cis-regulatory elements of orthologous genes. If this model is correct, a cis-regulatory element from one organism would be expected to function in a distantly related organism. To test this hypothesis, we fused the green fluorescent protein gene to neuronal and muscular enhancer elements from a variety of Drosophila melanogaster genes, and tested whether these would activate expression in the homologous cell types in Caenorhabditis elegans. Regulatory elements from several genes directed appropriate expression in homologous tissue types, suggesting conservation of regulatory sites. However, enhancers of most Drosophila genes tested were not properly recognized in C elegans, implying that over this evolutionary distance enough changes occurred in cis-regulatory sequences and/or transcription factors to prevent proper recognition of heterospecific enhancers. Comparisons of enhancer elements of orthologous genes between C. elegans and C. briggsae revealed extensive conservation, as well as specific instances of functional divergence. Our results indicate that functional changes in cis-regulatory sequences accumulate on timescales much shorter than the divergence of arthropods and nematodes, and that mechanisms other than conservation of individual binding sites within enhancer elements are responsible for the conservation of expression patterns of homologous genes between distantly related species.

Ruvinsky I et al. (2007) Dev Biol "Detection of broadly expressed neuronal genes in C. elegans."

Ohler U, Burge CB, Ruvkun G, Ruvinsky I

[Dev Biol, 2007]

The genes that are expressed in most or all types of neurons define generic neuronal features and provide a window into the developmental origin and function of the nervous system. Few such genes (sometimes referred to as pan-neuronal or broadly expressed neuronal genes) have been defined to date and the mechanisms controlling their regulation are not well understood. As a first step in investigating their regulation, we used a computational approach to detect sequences overrepresented in their promoter elements. We identified a ten-nucleotide cis-regulatory motif shared by many broadly expressed neuronal genes and demonstrated that it is involved in control of neuronal expression. Our results further suggest that global and cell-type-specific controls likely act in concert to establish pan-neuronal gene expression. Using the newly discovered motif and genome-level gene expression data, we identified a set of 234 candidate broadly expressed genes. The known involvement of many of these genes in neurogenesis and physiology of the nervous system supports the utility of this set for future targeted analyses.

Ruvinsky, I. et al. (2019) International Worm Meeting "Age-appropriate coordination of behavior and reproductive physiology via a shared neuronal circuit."

Aprison, E., Ruvinsky, I.

[International Worm Meeting, 2019]

Successful reproduction in animals involves orchestration of numerous behaviors and physiological processes. Because sex pheromones can induce both "releaser" (behavioral) and "priming" (physiological) effects, understanding how the nervous system processes these signals could illuminate the mechanisms that coordinate suites of reproduction-related traits. Here we describe a neuronal circuit that plays a central role in coupling behavior and the reproductive system in adult Caenorhabditis elegans hermaphrodites. We found that serotonin signal from NSM and HSN neurons that acts via the mod-1 receptor in AIY and RIF interneurons, and is antagonized by pigment-dispersing factor (PDF) signaling, is required for the response of the oogenic germline to the male pheromone. Surprisingly, the same circuit has been previously implicated in regulation of exploratory behavior in the absence of male-produced signals. We demonstrate that this circuit promotes an internal state that also reduces exploration and decreases mating latency. Thus, the circuit tunes fitness-proximal processes, germline physiology and behavior, that unfold on different time scales. Critically, only sexually mature hermaphrodites with a functional egg-laying apparatus modify their behavior in response to male pheromone. This is due to feedback from the vulva muscles that reports ongoing reproduction to the nervous system. Our results demonstrate a mechanism by which a single circuit could coordinate distinct responses to the environment and reveal an activity-dependent conduit by which the reproductive system continuously licenses adult responses to the pheromones of the opposite sex.

McGrath PT et al. (2019) Curr Opin Syst Biol "A primer on pheromone signaling in Caenorhabditis elegans for systems biologists."

Ruvinsky I, McGrath PT

[Curr Opin Syst Biol, 2019]

<i>Individuals communicate information about their age, sex, social status, and recent life history with other members of their species through the release of pheromones, chemical signals that elicit behavioral or physiological changes in the recipients. Pheromones provide a fascinating example of information exchange: animals have evolved intraspecific languages in the presence of eavesdroppers and cheaters. In this review, we discuss the recent work using the nematode</i> C. elegans <i>to decipher its chemical language through the analysis of ascaroside pheromones. Genetic dissection has started to identify the enzymes that produce pheromones and the neural circuits that process these signals. Ecological experiments have characterized the biotic environment of</i> C. elegans <i>and its relatives, including ecological relationships with a variety of species that sense or release similar blends of ascarosides. Systems biology approaches should be fruitful in understanding the organization and function of communication systems in</i> C. elegans.

Aprison EZ et al. (2019) Curr Biol "Dynamic Regulation of Adult-Specific Functions of the Nervous System by Signaling from the Reproductive System."

Ruvinsky I, Aprison EZ

[Curr Biol, 2019]

Unlike juveniles, adult animals engage in suites of behaviors related to the search for and selection of potential mates and mating, including appropriate responses to sex pheromones. As in other species [1], male sex pheromones modulate several behaviors and physiological processes in C.elegans hermaphrodites [2-5]. In particular, one of these small-molecule signals, an ascaroside ascr#10, causes reduced exploration, more avid mating, and improved reproductive performance (see the accompanying paper by Aprison and Ruvinsky in this issue of Current Biology) [6]. Here, we investigated the mechanism that restricts pheromone response to adult hermaphrodites. Unexpectedly, we found that attainment of developmental adulthood was not alone sufficient for the behavioral response to the pheromone. To modify exploratory behavior in response to male pheromone, adult hermaphrodites also require functional germline and egg-laying apparatus. We show that this dependence of behavior on the reproductive system is due to feedback from the vulva muscles that reports ongoing reproduction to the nervous system. Our results reveal an activity-dependent conduit by which the reproductive system continuously licenses adult behaviors, including appropriate responses to the pheromones of the opposite sex. More broadly, our results suggest that signals from peripheral organs may serve as an important component of assuring age-appropriate functions of the nervous system.

Aprison EZ et al. (2022) Proc Biol Sci "The serotonin circuit that coordinates germline proliferation and egg laying with other reproductive functions in Caenorhabditis elegans."

Dzitoyeva S, Aprison EZ, Ruvinsky I

[Proc Biol Sci, 2022]

Behaviour and physiology are altered in reproducing animals, but neuronal circuits that regulate these changes remain largely unknown. Insights into mechanisms that regulate and possibly coordinate reproduction-related traits could be gleaned from the study of sex pheromones that can improve the reproductive success of potential mating partners. In <i>Caenorhabditis elegans</i>, the prominent male pheromone, ascr#10, modifies reproductive behaviour and several aspects of reproductive physiology in hermaphrodite recipients, including improving oocyte quality. Here we show that a circuit that contains serotonin-producing and serotonin-uptaking neurons plays a key role in mediating effects of ascr#10 on germline development and egg laying behaviour. We also demonstrate that increased serotonin signalling promotes proliferation of germline progenitors in adult hermaphrodites. Our results establish a role for serotonin in maintaining germline quality and highlight a simple neuronal circuit that acts as a linchpin that couples food intake, mating behaviour, reproductive output, and germline renewal and provisioning.

Aprison EZ et al. (2022) MicroPubl Biol

Aprison EZ, Ruvinsky I

[MicroPubl Biol, 2022]

Valence of animal pheromone blends can vary due to differences in relative abundance of individual components. For example, in C. elegans, whether a pheromone blend is perceived as "male" or "hermaphrodite" is determined by the ratio of concentrations of ascr#10 and ascr#3. The neuronal mechanisms that evaluate this ratio are not currently understood. We present data that suggest that the function of guanylyl cyclase ODR-1 in AWB neurons is required for the effect of ascr#3 that counteracts the activity of ascr#10. This finding defines a new module in the neuronal mechanism that determines the sexual identity of C. elegans pheromone.

Wang PP et al. (2010) RNA "Computational prediction of Caenorhabditis box H/ACA snoRNAs using genomic properties of their host genes."

Ruvinsky I, Wang PP

[RNA, 2010]

Identification of small nucleolar RNAs (snoRNAs) in genomic sequences has been challenging due to the relative paucity of sequence features. Many current prediction algorithms rely on detection of snoRNA motifs complementary to target sites in snRNAs and rRNAs. However, recent discovery of snoRNAs without apparent targets requires development of alternative prediction methods. We present an approach that combines rule-based filters and a Bayesian Classifier to identify a class of snoRNAs (H/ACA) without requiring target sequence information. It takes advantage of unique attributes of their genomic organization and improved species-specific motif characterization to predict snoRNAs that may otherwise be difficult to discover. Searches in the genomes of Caenorhabditis elegans and the closely related Caenorhabditis briggsae suggest that our method performs well compared to recent benchmark algorithms. Our results illustrate the benefits of training gene discovery engines on features restricted to particular phylogenetic groups and the utility of incorporating diverse data types in gene prediction.

Aprison EZ et al. (2014) PLoS One "Balanced trade-offs between alternative strategies shape the response of C. elegans reproduction to chronic heat stress."

Ruvinsky I, Aprison EZ

[PLoS One, 2014]

To ensure long-term reproductive success organisms have to cope with harsh environmental extremes. A reproductive strategy that simply maximizes offspring production is likely to be disadvantageous because it could lead to a catastrophic loss of fecundity under unfavorable conditions. To understand how an appropriate balance is achieved, we investigated reproductive performance of C. elegans under conditions of chronic heat stress. We found that following even prolonged exposure to temperatures at which none of the offspring survive, worms could recover and resume reproduction. The likelihood of producing viable offspring falls precipitously after exposure to temperatures greater than 28C primarily due to sperm damage. Surprisingly, we found that worms that experienced higher temperatures can recover considerably better, provided they did not initiate ovulation. Therefore mechanisms controlling this process must play a crucial role in determining the probability of recovery. We show, however, that suppressing ovulation is only beneficial under relatively long stresses, whereas it is a disadvantageous strategy under shorter stresses of the same intensity. This is because the benefit of shutting down egg laying, and thus protecting the reproductive system, is negated by the cost associated with implementing this strategy--it takes considerable time to recover and produce offspring. We interpret these balanced trade-offs as a dynamic response of the C. elegans reproductive system to stress and an adaptation to life in variable and unpredictable conditions.

Aprison, E. et al. (2017) International Worm Meeting "Sexually antagonistic male signals manipulate germline and soma of C. elegans hermaphrodites."

Aprison, E., Ruvinsky, I.

[International Worm Meeting, 2017]

Males and females pursue different reproductive strategies, which often bring them into conflict - many traits exist that benefit one sex at a cost to another. Decreased female survival following mating dramatically demonstrates one aspect of this phenomenon. Particularly intriguing is the evidence that secreted compounds can shorten lifespan of members of the opposite sex in Drosophila and Caenorhabditid nematodes even without copulation taking place. The purpose of such signals is not clear, however. While it is possible that they could limit subsequent mating with competitors or hasten post-reproductive demise, thus decreasing competition for resources, they are also likely to harm unmated individuals. Why would a system exist that reduces the vigor of potential mates prior to mating? Addressing this question could provide insights into mechanisms and evolution of sexual conflict and reveal sensory inputs that regulate aging. We describe two distinct ways in which C. elegans males cause faster somatic aging of hermaphrodites, but also manipulate different aspects of their reproductive physiology. The first, mediated by conserved ascaroside pheromones, delays the loss of germline progenitor cells. The second accelerates development, resulting in faster sexual maturation. These signals promote male reproductive strategy and the effects harmful to hermaphrodites appear to be collateral damage rather than the goal.