RESUMO
To bring about sexual dimorphism in form, information from the sex determination pathway must trigger sex-specific modifications in developmental programs. DM-domain encoding genes have been found to be involved in sex determination in a multitude of animals, often at the level of male somatic gonad formation. Here we report our findings that the DM-domain transcription factors MAB-3 and DMD-3 function together in multiple steps during the late stages of C. elegans male somatic gonad development. Both mab-3 and dmd-3 are expressed in the linker cell and hindgut of L4 males and dmd-3 is also expressed in presumptive vas deferens cells. Furthermore, dmd-3, but not mab-3, expression in the linker cell is downstream of nhr-67, a nuclear hormone receptor that was previously shown to control late stages of linker cell migration. In mab-3; dmd-3 double mutant males, the last stage of linker cell migration is partially defective, resulting in aberrant linker cell shapes and often a failure of the linker cell to complete its migration to the hindgut. When mab-3; dmd-3 double mutant linker cells do complete their migration, they fail to be engulfed by the hindgut, indicating that dmd-3 and mab-3 activity are essential for this process. Furthermore, linker cell death and clearance are delayed in mab-3; dmd-3 double mutants, resulting in the linker cell persisting into adulthood. Finally, DMD-3 and MAB-3 function to activate expression of the bZIP transcription factor encoding gene zip-5 and downregulate the expression of the zinc metalloprotease ZMP-1 in the linker cell. Taken together, these results demonstrate a requirement for DM-domain transcription factors in controlling C. elegans male gonad formation, supporting the notion that the earliest DM-domain genes were involved in male somatic gonad development in the last common ancestor of the bilaterians.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Regulação da Expressão Gênica no Desenvolvimento , Animais , Masculino , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Movimento Celular/genética , Proteínas de Ligação a DNA , Gônadas/metabolismo , Mutação/genética , Processos de Determinação Sexual/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genéticaRESUMO
Many 'hard-wired', innate animal behaviors are related to reproduction. So what happens when reproductive systems evolve? New research in nematodes has identified principles underlying the co-evolution of reproductive strategy and sexual behavior, revealing some surprises and raising intriguing new questions.
Assuntos
Evolução Biológica , Comportamento Sexual Animal , Animais , Comportamento Sexual Animal/fisiologia , Reprodução , Organismos Hermafroditas/fisiologia , Caenorhabditis elegans/fisiologia , Masculino , FemininoRESUMO
For sexually reproducing animals, selecting optimal mates is important for maximizing reproductive fitness. In the nematode C. elegans, populations reproduce largely by hermaphrodite self-fertilization, but the cross-fertilization of hermaphrodites by males also occurs. Males' ability to recognize hermaphrodites involves several sensory cues, but an integrated view of the ways males use these cues in their native context to assess characteristics of potential mates has been elusive. Here, we examine the mate-preference behavior of C. elegans males evoked by natively produced cues. We find that males use a combination of volatile sex pheromones (VSPs), ascaroside sex pheromones, surface-associated cues, and other signals to assess multiple features of potential mates. Specific aspects of mate preference are communicated by distinct signals: developmental stage and sex are signaled by ascaroside pheromones and surface cues, whereas the presence of a self-sperm-depleted hermaphrodite is likely signaled by VSPs. Furthermore, males prefer to interact with virgin over mated, and well-fed over food-deprived, hermaphrodites; these preferences are likely adaptive and are also mediated by ascarosides and other cues. Sex-typical mate-preference behavior depends on the sexual state of the nervous system, such that pan-neuronal genetic masculinization in hermaphrodites generates male-typical social behavior. We also identify an unexpected role for the sex-shared ASH sensory neurons in male attraction to ascaroside sex pheromones. Our findings lead to an integrated view in which the distinct physical properties of various mate-preference cues guide a flexible, stepwise behavioral program by which males assess multiple features of potential mates to optimize mate preference.
Assuntos
Caenorhabditis elegans , Atrativos Sexuais , Animais , Feminino , Masculino , Caenorhabditis elegans/fisiologia , Sinais (Psicologia) , Sêmen , Comportamento Sexual Animal/fisiologia , Feromônios/fisiologia , Células Receptoras SensoriaisRESUMO
Neurons must access the environment to gather information, but this exposure must be carefully managed. New work finds that glial cells, the non-neuronal component of the nervous system, control environmental access by stage- and sex-specific patterning of the extracellular matrix.
Assuntos
Neuroglia , Neurônios , Masculino , Feminino , Humanos , Neurônios/fisiologia , Neuroglia/fisiologia , Matriz Extracelular/fisiologia , Biologia do DesenvolvimentoRESUMO
For sexually reproducing animals, selecting optimal mates is essential for maximizing reproductive fitness. Because the nematode C. elegans reproduces mostly by self-fertilization, little is known about its mate-choice behaviors. While several sensory cues have been implicated in males' ability to recognize hermaphrodites, achieving an integrated understanding of the ways males use these cues to assess relevant characteristics of potential mates has proven challenging. Here, we use a choice-based social-interaction assay to explore the ability of C. elegans males to make and optimize mate choices. We find that males use a combination of volatile sex pheromones (VSPs), ascaroside pheromones, surface-bound chemical cues, and other signals to robustly assess a variety of features of potential mates. Specific aspects of mate choice are communicated by distinct signals: the presence of a sperm-depleted, receptive hermaphrodite is likely signaled by VSPs, while developmental stage and sex are redundantly specified by ascaroside pheromones and surface-associated cues. Ascarosides also signal nutritional information, allowing males to choose well-fed over starved mates, while both ascarosides and surface-associated cues cause males to prefer virgin over previously mated hermaphrodites. The male-specificity of these behavioral responses is determined by both male-specific neurons and the male state of sex-shared circuits, and we reveal an unexpected role for the sex-shared ASH sensory neurons in male attraction to endogenously produced hermaphrodite ascarosides. Together, our findings lead to an integrated view of the signaling and behavioral mechanisms by which males use diverse sensory cues to assess multiple features of potential mates and optimize mate choice.
RESUMO
Recent studies of animal metabolism have revealed large numbers of novel metabolites that are involved in all aspects of organismal biology, but it is unclear to what extent metabolomes differ between sexes. Here, using untargeted comparative metabolomics for the analysis of wildtype animals and sex determination mutants, we show that C. elegans hermaphrodites and males exhibit pervasive metabolomic differences. Several hundred small molecules are produced exclusively or in much larger amounts in one sex, including a host of previously unreported metabolites that incorporate building blocks from nucleoside, carbohydrate, lipid, and amino acid metabolism. A subset of male-enriched metabolites is specifically associated with the presence of a male germline, whereas enrichment of other compounds requires a male soma. Further, we show that one of the male germline-dependent metabolites, an unusual dipeptide incorporating N,N-dimethyltryptophan, increases food consumption, reduces lifespan, and accelerates the last stage of larval development in hermaphrodites. Our results serve as a foundation for mechanistic studies of how the genetic sex of soma and germline shape the C. elegans metabolome and provide a blueprint for the discovery of sex-dependent metabolites in other animals.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Masculino , Caenorhabditis elegans/metabolismo , Metaboloma , Proteínas de Caenorhabditis elegans/metabolismo , Metabolômica/métodos , LongevidadeRESUMO
The effect of the detailed connectivity of a neural circuit on its function and the resulting behavior of the organism is a key question in many neural systems. Here, we study the circuit for nociception in C. elegans, which is composed of the same neurons in the two sexes that are wired differently. We show that the nociceptive sensory neurons respond similarly in the two sexes, yet the animals display sexually dimorphic behaviors to the same aversive stimuli. To uncover the role of the downstream network topology in shaping behavior, we learn and simulate network models that replicate the observed dimorphic behaviors and use them to predict simple network rewirings that would switch behavior between the sexes. We then show experimentally that these subtle synaptic rewirings indeed flip behavior. Interestingly, when presented with aversive cues, rewired males were compromised in finding mating partners, suggesting that network topologies that enable efficient avoidance of noxious cues have a reproductive "cost." Our results present a deconstruction of the design of a neural circuit that controls sexual behavior and how to reprogram it.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Masculino , Caenorhabditis elegans/fisiologia , Proteínas de Caenorhabditis elegans/fisiologia , Nociceptividade , Sistema Nervoso , Células Receptoras Sensoriais/fisiologiaRESUMO
To make adaptive feeding and foraging decisions, animals must integrate diverse sensory streams with multiple dimensions of internal state. In C. elegans, foraging and dispersal behaviors are influenced by food abundance, population density, and biological sex, but the neural and genetic mechanisms that integrate these signals are poorly understood. Here, by systematically varying food abundance, we find that chronic avoidance of the population-density pheromone ascr#3 is modulated by food thickness, such that hermaphrodites avoid ascr#3 only when food is scarce. The integration of food and pheromone signals requires the conserved neuropeptide receptor PDFR-1, as pdfr-1 mutant hermaphrodites display strong ascr#3 avoidance, even when food is abundant. Conversely, increasing PDFR-1 signaling inhibits ascr#3 aversion when food is sparse, indicating that this signal encodes information about food abundance. In both wild-type and pdfr-1 hermaphrodites, chronic ascr#3 avoidance requires the ASI sensory neurons. In contrast, PDFR-1 acts in interneurons, suggesting that it modulates processing of the ascr#3 signal. Although a sex-shared mechanism mediates ascr#3 avoidance, food thickness modulates this behavior only in hermaphrodites, indicating that PDFR-1 signaling has distinct functions in the two sexes. Supporting the idea that this mechanism modulates foraging behavior, ascr#3 promotes ASI-dependent dispersal of hermaphrodites from food, an effect that is markedly enhanced when food is scarce. Together, these findings identify a neurogenetic mechanism that sex-specifically integrates population and food abundance, two important dimensions of environmental quality, to optimize foraging decisions. Further, they suggest that modulation of attention to sensory signals could be an ancient, conserved function of pdfr-1.
Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Feminino , Masculino , Feromônios , Células Receptoras Sensoriais/fisiologia , Transdução de Sinais , Fatores de TranscriçãoRESUMO
For the first 25 years after the landmark 1974 paper that launched the field, most C. elegans biologists were content to think of their subjects as solitary creatures. C. elegans presented no shortage of fascinating biological problems, but some of the features that led Brenner to settle on this species-in particular, its free-living, self-fertilizing lifestyle-also seemed to reduce its potential for interesting social behavior. That perspective soon changed, with the last two decades bringing remarkable progress in identifying and understanding the complex interactions between worms. The growing appreciation that C. elegans behavior can only be meaningfully understood in the context of its ecology and evolution ensures that the coming years will see similarly exciting progress.
Assuntos
Caenorhabditis elegans/fisiologia , Etologia/história , Organismos Hermafroditas/fisiologia , Animais , Comportamento Alimentar/fisiologia , Feminino , Glicolipídeos/fisiologia , História do Século XX , História do Século XXI , Masculino , Feromônios/fisiologia , Comportamento Sexual Animal/fisiologia , Comportamento SocialRESUMO
Biological sex in animals is often considered a fixed, individual-level characteristic. However, not all sex-specific features are static: for example, C. elegans males (XO) can sometimes exhibit hermaphrodite (XX)-like feeding behavior [1, 2]. (C. elegans hermaphrodites are somatic females that transiently produce self-sperm.) Essentially all somatic sex differences in C. elegans are governed by the master regulator tra-1, whose activity is controlled by chromosomal sex and is necessary and sufficient to specify the hermaphrodite state [3]. One aspect of this state is high expression of the chemoreceptor odr-10. In hermaphrodites, high odr-10 expression promotes feeding, but in males, low odr-10 expression facilitates exploration [4]. However, males suppress this sex difference in two contexts: juvenile males exhibit high odr-10 expression and food deprivation activates odr-10 in adult males [4-6]. Remarkably, we find that both of these phenomena require tra-1. In juvenile (L3) males, tra-1 is expressed in numerous neurons; this expression diminishes as individuals mature into adulthood, a process that requires conserved regulators of sexual maturation. tra-1 remains expressed in a small number of neurons in adult males, where it likely has a permissive role in odr-10 activation. Thus, the neuronal functions of tra-1 are not limited to hermaphrodites; rather, tra-1 also acts in the male nervous system to transiently suppress a sexual dimorphism, developmentally and in response to nutritional stress. Our results show that the molecular and functional representation of sexual state in C. elegans is neither static nor homogeneous, challenging traditional notions about the nature of biological sex.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/fisiologia , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Sistema Nervoso/metabolismo , Receptores Citoplasmáticos e Nucleares/metabolismo , Caracteres Sexuais , Fatores de Transcrição/metabolismo , Animais , Proteínas de Caenorhabditis elegans/genética , Proteínas de Ligação a DNA/genética , Feminino , Masculino , Sistema Nervoso/citologia , Receptores Citoplasmáticos e Nucleares/genética , Fatores Sexuais , Fatores de Transcrição/genéticaRESUMO
Dynamic integration of internal and external cues is essential for flexible, adaptive behavior. In C. elegans, biological sex and feeding state regulate expression of the food-associated chemoreceptor odr-10, contributing to plasticity in food detection and the decision between feeding and exploration. In adult hermaphrodites, odr-10 expression is high, but in well-fed adult males, odr-10 expression is low, promoting exploratory mate-searching behavior. Food-deprivation transiently activates male odr-10 expression, heightening food sensitivity and reducing food leaving. Here, we identify a neuroendocrine feedback loop that sex-specifically regulates odr-10 in response to food deprivation. In well-fed males, insulin-like (insulin/IGF-1 signaling [IIS]) and transforming growth factor ß (TGF-ß) signaling repress odr-10 expression. Upon food deprivation, odr-10 is directly activated by DAF-16/FoxO, the canonical C. elegans IIS effector. The TGF-ß ligand DAF-7 likely acts upstream of IIS and links feeding to odr-10 only in males, due in part to the male-specific expression of daf-7 in ASJ. Surprisingly, these responses to food deprivation are not triggered by internal metabolic cues but rather by the loss of sensory signals associated with food. When males are starved in the presence of inedible food, they become nutritionally stressed, but odr-10 expression remains low and exploratory behavior is suppressed less than in starved control males. Food signals are detected by a small number of sensory neurons whose activity non-autonomously regulates daf-7 expression, IIS, and odr-10. Thus, adult C. elegans males employ a neuroendocrine feedback loop that integrates food detection and genetic sex to dynamically modulate chemoreceptor expression and influence the feeding-versus-exploration decision.
Assuntos
Comportamento Animal/fisiologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/fisiologia , Comportamento Alimentar/fisiologia , Sensação/genética , Sensação/fisiologia , Caracteres Sexuais , Animais , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/fisiologia , Fatores de Transcrição Forkhead/metabolismo , Insulina/metabolismo , Masculino , Receptores Odorantes/metabolismo , Receptores Odorantes/fisiologia , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismoAssuntos
Caenorhabditis elegans/citologia , Neurociências/história , Animais , Linhagem da Célula , Biologia do Desenvolvimento/história , Inglaterra , História do Século XX , Humanos , Modelos Animais , Modelos Neurológicos , Sistema Nervoso/citologia , Neuroglia/fisiologia , Neurônios/fisiologia , Prêmio Nobel , Especificidade da EspécieRESUMO
Sexual maturation must occur on a controlled developmental schedule. In mammals, Makorin3 (MKRN3) and the miRNA regulators LIN28A/B are key regulators of this process, but how they act is unclear. In C. elegans, sexual maturation of the nervous system includes the functional remodeling of postmitotic neurons and the onset of adult-specific behaviors. Here, we find that the lin-28-let-7 axis (the 'heterochronic pathway') determines the timing of these events. Upstream of lin-28, the Makorin lep-2 and the lncRNA lep-5 regulate maturation cell-autonomously, indicating that distributed clocks, not a central timer, coordinate sexual differentiation of the C. elegans nervous system. Overexpression of human MKRN3 delays aspects of C. elegans sexual maturation, suggesting the conservation of Makorin function. These studies reveal roles for a Makorin and a lncRNA in timing of sexual differentiation; moreover, they demonstrate deep conservation of the lin-28-let-7 system in controlling the functional maturation of the nervous system.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Caenorhabditis elegans/genética , RNA Longo não Codificante/genética , Proteínas Repressoras/genética , Ribonucleoproteínas/genética , Animais , Caenorhabditis elegans/crescimento & desenvolvimento , Diferenciação Celular , Regulação da Expressão Gênica no Desenvolvimento , Humanos , MicroRNAs , Mutação , Sistema Nervoso/crescimento & desenvolvimento , Maturidade Sexual/genética , Ubiquitina-Proteína LigasesAssuntos
Conectoma , Animais , Caenorhabditis elegans , Feminino , Masculino , Modelos Neurológicos , Redes Neurais de ComputaçãoRESUMO
Biological roles for most long non-coding RNAs (lncRNAs) remain mysterious. Here, using forward genetics, we identify lep-5, a lncRNA acting in the C. elegans heterochronic (developmental timing) pathway. Loss of lep-5 delays hypodermal maturation and male tail tip morphogenesis (TTM), hallmarks of the juvenile-to-adult transition. We find that lep-5 is a â¼600 nt cytoplasmic RNA that is conserved across Caenorhabditis and possesses three essential secondary structure motifs but no essential open reading frames. lep-5 expression is temporally controlled, peaking prior to TTM onset. Like the Makorin LEP-2, lep-5 facilitates the degradation of LIN-28, a conserved miRNA regulator specifying the juvenile state. Both LIN-28 and LEP-2 associate with lep-5 in vivo, suggesting that lep-5 directly regulates LIN-28 stability and may function as an RNA scaffold. These studies identify a key biological role for a lncRNA: by regulating protein stability, it provides a temporal cue to facilitate the juvenile-to-adult transition.
Assuntos
Proteínas de Caenorhabditis elegans/metabolismo , Caenorhabditis elegans/crescimento & desenvolvimento , RNA Longo não Codificante/metabolismo , Proteínas Repressoras/metabolismo , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Morfogênese/genética , Morfogênese/fisiologia , Mutação , Fenótipo , RNA Longo não Codificante/genética , Proteínas Repressoras/genética , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo , Fatores de Transcrição/metabolismoRESUMO
The molecular mechanisms that control the timing of sexual differentiation in the brain are poorly understood. We found that the timing of sexually dimorphic differentiation of postmitotic, sex-shared neurons in the nervous system of the Caenorhabditis elegans male is controlled by the temporally regulated miRNA let-7 and its target lin-41, a translational regulator. lin-41 acts through lin-29a, an isoform of a conserved Zn finger transcription factor, expressed in a subset of sex-shared neurons only in the male. Ectopic lin-29a is sufficient to impose male-specific features at earlier stages of development and in the opposite sex. The temporal, sexual and spatial specificity of lin-29a expression is controlled intersectionally through the lin-28/let-7/lin-41 heterochronic pathway, sex chromosome configuration and neuron-type-specific terminal selector transcription factors. Two Doublesex-like transcription factors represent additional sex- and neuron-type specific targets of LIN-41 and are regulated in a similar intersectional manner.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Diferenciação Celular/genética , MicroRNAs/genética , Sistema Nervoso/metabolismo , Neurônios/metabolismo , Fatores de Transcrição/genética , Sequência de Aminoácidos , Animais , Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Larva/genética , Larva/crescimento & desenvolvimento , Larva/metabolismo , Masculino , Sistema Nervoso/citologia , Homologia de Sequência de Aminoácidos , Diferenciação Sexual/genética , Fatores Sexuais , Fatores de Tempo , Fatores de Transcrição/metabolismoRESUMO
As fundamental features of nearly all animal species, sexual dimorphisms and sex differences have particular relevance for the development and function of the nervous system. The unique advantages of the nematode Caenorhabditis elegans have allowed the neurobiology of sex to be studied at unprecedented scale, linking ultrastructure, molecular genetics, cell biology, development, neural circuit function, and behavior. Sex differences in the C. elegans nervous system encompass prominent anatomical dimorphisms as well as differences in physiology and connectivity. The influence of sex on behavior is just as diverse, with biological sex programming innate sex-specific behaviors and modifying many other aspects of neural circuit function. The study of these differences has provided important insights into mechanisms of neurogenesis, cell fate specification, and differentiation; synaptogenesis and connectivity; principles of circuit function, plasticity, and behavior; social communication; and many other areas of modern neurobiology.
Assuntos
Caenorhabditis elegans/anatomia & histologia , Caenorhabditis elegans/fisiologia , Neurogênese , Neurônios/metabolismo , Caracteres Sexuais , Comportamento Sexual Animal , Animais , Diferenciação Celular , Linhagem da Célula , Organogênese , Desenvolvimento SexualRESUMO
Biological sex, a fundamental dimension of internal state, can modulate neural circuits to generate behavioral variation. Understanding how and why circuits are tuned by sex can provide important insights into neural and behavioral plasticity. Here we find that sexually dimorphic behavioral responses to C. elegans ascaroside sex pheromones are implemented by the functional modulation of shared chemosensory circuitry. In particular, the sexual state of a single sensory neuron pair, ADF, determines the nature of an animal's behavioral response regardless of the sex of the rest of the body. Genetic feminization of ADF causes males to be repelled by, rather than attracted to, ascarosides, whereas masculinization of ADF has the opposite effect in hermaphrodites. When ADF is ablated, both sexes are weakly repelled by ascarosides. Genetic sex modulates ADF function by tuning chemosensation: although ADF is functional in both sexes, it detects the ascaroside ascr#3 only in males, a consequence of cell-autonomous action of the master sexual regulator tra-1. This occurs in part through the conserved DM-domain gene mab-3, which promotes the male state of ADF. The sexual modulation of ADF has a key role in reproductive fitness, as feminization or ablation of ADF renders males unable to use ascarosides to locate mates. Our results reveal an economical mechanism in which sex-specific behavioral valence arises through the cell-autonomous regulation of a chemosensory switch by genetic sex, allowing a social cue with salience for both sexes to elicit navigational responses commensurate with the differing needs of each.
Assuntos
Aptidão Genética/fisiologia , Células Receptoras Sensoriais/fisiologia , Animais , Comportamento Animal/fisiologia , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/fisiologia , Células Quimiorreceptoras/metabolismo , Proteínas de Ligação a DNA/metabolismo , Proteínas de Ligação a DNA/fisiologia , Feminino , Masculino , Sistema Nervoso , Neurônios/fisiologia , Células Receptoras Sensoriais/metabolismo , Atrativos Sexuais/metabolismo , Caracteres Sexuais , Comportamento Sexual Animal/fisiologia , Fatores de Transcrição/genéticaRESUMO
Studies using the nematode C. elegans have provided unique insights into the development and function of sex differences in the nervous system. Enabled by the relative simplicity of this species, comprehensive studies have solved the complete cellular neuroanatomy of both sexes as well as the complete neural connectomes of the entire adult hermaphrodite and the adult male tail. This work, together with detailed behavioral studies, has revealed three aspects of sex differences in the nervous system: sex-specific neurons and circuits; circuits with sexually dimorphic synaptic connectivity; and sex differences in the physiology and functions of shared neurons and circuits. At all of these levels, biological sex influences neural development and function through the activity of a well-defined genetic hierarchy that acts throughout the body to translate chromosomal sex into the state of a master autosomal regulator of sexual differentiation, the transcription factor TRA-1A. This Review focuses on the role of genetic sex in implementing sex differences in shared neurons and circuits, with an emphasis on linking the sexual modulation of specific neural properties to the specification and optimization of sexually divergent and dimorphic behaviors. An important and unexpected finding from these studies is that chemosensory neurons are a primary focus of sexual modulation, with genetic sex adaptively shaping chemosensory repertoire to guide behavioral choice. Importantly, hormone-independent functions of genetic sex are the principal drivers of all of these sex differences, making nematodes an excellent model for understanding similar but poorly understood mechanisms that likely act throughout the animal kingdom. © 2016 Wiley Periodicals, Inc.