Biology subjects

Oren-Suissa, M.

Publications and source records attributed to Oren-Suissa, M..

10 recordsLinked to original sources

bioRxiv2026

A panoramic view of the expression and function of the Doublesex/DMRT gene family in C. elegans

Throughout the animal kingdom, sex determination and sexual differentiation are orchestrated by a strikingly diverse set of regulatory factors. The only type of molecules consistently deployed during sexual differentiation are members of the Doublesex/Mab-3-related transcription factor (DMRT) family. Although each animal genome codes for a multitude of DMRT family members, in no species has the full array of DMRT genes been comprehensively analyzed across the entire animal, in all sexes and throughout development. Hence, the extent of deployment of DMRT genes in sexual differentiation remains unknown. We describe here the first genome- and nervous system-wide expression and functional analysis of all members of the DMRT gene family. Leveraging genome-engineered reporter alleles of all ten DMRT genes of the nematode Caenorhabditis elegans, we find that six DMRTs display sexually dimorphic expression in somatic and/or reproductive tissues, including in cell and tissue types not previously known to be sexually dimorphic. In the nervous system, DMRT protein expression covers many, though not all, known sexually dimorphic neuron types. Analyses of DMRT null mutant alleles reveal a suite of neuronal differentiation defects, ranging from altered neurotransmitter identities and switched neuropeptide signatures to impaired glia-to-neuron transdifferentiation. Several DMRT proteins do not exhibit sexually dimorphic expression, indicating roles beyond sexual differentiation. Similar comprehensive analyses of DMRT genes in other organisms may help to better understand the extent and regulation of sex-specific cellular differentiation programs.

developmental biology↗

bioRxiv2024

A Blueprint of Sex-Specific Neuronal Regulation in the C. elegans Nervous System at Single-Cell Resolution

Sex-specific behaviors are often attributed to differences in neuronal wiring and molecular composition, yet how genetic sex shapes the molecular architecture of the nervous system at the individual neuron level remains unclear. Here, we use single-cell RNA sequencing to profile the transcriptome of sex-shared neurons in adult Caenorhabditis elegans males and hermaphrodites. We uncover widespread molecular dimorphism across the nervous system, including in previously unrecognized neuron-types such as the touch receptors. Neuropeptides and signaling-related genes exhibit strong sex-biased expression, particularly in males, reinforcing the notion that neuropeptides are crucial for diversifying connectome outputs. Despite these differences, neurotransmitter identities remain largely conserved, indicating that functional dimorphism arises through modulatory, not identity-defining, changes. We show that sex-biased expression of neurotransmitter-related genes correlates with bias in outgoing synaptic connectivity and identify regulatory candidates for synaptic wiring, including both shared and sex-specific genes. This dataset provides a molecular framework for understanding how subtle regulatory differences tune conserved circuits to drive sex-specific behaviors.

neuroscience↗

bioRxiv2024

Perception of Temperature Even in the Absence of Actual Change is Sufficient to Drive Transgenerational Epigenetic Inheritance

Can processes occurring in one individuals nervous system influence the physiology of the descendants? Here, we explored the hypothesis that parents sensation or perception of environmental cues can influence their offspring, extending across many subsequent generations. We show that in Caenorhabditis elegans, temperature perception by the AFD thermosensory neurons initiates a signaling cascade that, directly or indirectly, induces transgenerational changes in RNAi factors, small RNAs, and their target genes. Moreover, we identify secreted factors that enable this neuron-to-germline communication and trace the path of the epigenetic signal. We further model the process mathematically, and the model yields new predictions that we validate experimentally: blocking sensory input dampens RNAi inheritance initiated by exogenous double-stranded RNA (dsRNA). Together, our results demonstrate that sensory perception is sufficient to influence small RNA-mediated heritable gene expression memory.

genetics↗

bioRxiv2024

A Tunable and Druggable Mechanism to Delay Forgetting of Olfactory Memories in C. elegans

The poet W.B Yeats wrote that "All that is personal soon rots, it must be packed in ice or salt". Here we show that in Caenorhabditis elegans nematodes, simple animals with just 302 neurons, memories are preserved on ice and in lithium salt. C. elegans nematodes can form associative memories, which are typically forgotten quickly. We discovered that when placed on ice, worms delay forgetting of specific olfactory memories by at least 8-fold. Delayed forgetting was canceled completely when the worms were gradually adapted to low temperatures, owing to a genetically-encoded program that turns acclimated worms cold-tolerant. RNA-seq, mutant analyses, and pharmacological assays revealed that regulation of membrane properties switches cold-induced delayed forgetting ON and OFF, and, remarkably, that lithium delays forgetting only in cold-sensitive but not cold-tolerant worms. We found that downregulation of the diacylglycerol pathway in the AWC sensory neurons is essential for lithium-mediated delayed forgetting, and using neuronal activity recordings located the memory trace to the downstream AIY interneurons. We suggest that the awesome genetic tractability of C. elegans might be harnessed to study the effects of lithium and cold temperatures on the brain, why it influences psychiatric disorders, and even more fundamentally how memory is stored and lost.

neuroscience↗

bioRxiv2023

Modulation by NPYR underlies experience-dependent, sexually dimorphic learning

The evolutionary paths taken by each sex within a given species sometimes diverge, resulting in behavioral differences. Given their distinct needs, the mechanism by which each sex learns from a shared experience is still an open question. Here, we reveal sexual dimorphism in learning: C. elegans males do not learn to avoid the pathogenic bacteria PA14 as efficiently and rapidly as hermaphrodites. Notably, neuronal activity following pathogen exposure was dimorphic: hermaphrodites generate robust representations, while males, in line with their behavior, exhibit contrasting representations. Transcriptomic and behavioral analysis revealed that the neuropeptide receptor npr-5, an ortholog of the mammalian NPY receptor, regulates male learning by modulating neuronal activity. Furthermore, we show the dependency of the males decision-making on their sexual status and demonstrate the pivotal role of npr-5 as a modulator of incoming sensory cues. Taken together, we portray sex-specific plasticity in behavior toward a shared experience by modulating learning.

neuroscience↗

bioRxiv2023

Sex-Specific Developmental Gene Expression Atlas Unveils Dimorphic Gene Networks in C. elegans

Sex-specific traits and behaviors emerge during development by the acquisition of unique properties in the nervous system of each sex. However, the genetic events responsible for introducing these sex-specific features remain poorly understood. In this study, we created a comprehensive gene expression atlas for both sexes of the nematode Caenorhabditis elegans across development. By comparing the transcriptome of pure populations of hermaphrodites and males from early larval stages to adulthood, we discovered numerous differentially expressed genes, including neuronal gene families like transcription factors, neuropeptides, and GPCRs. We identified INS-39, an insulin-like peptide, as a prominent male-biased gene expressed specifically in ciliated sensory neurons. We show that INS-39 serves as an early-stage male marker, facilitating the effective isolation of males in high-throughput experiments. Through complex and sex-specific regulation, ins-39 plays pleiotropic sexually-dimorphic roles in temperature sensation, survival in cold temperatures, resilience against high hydrogen peroxide levels, and dauer entry, while also playing a shared, dimorphic role in early life stress. This study offers a comparative sexual and developmental gene expression database for C. elegans, which will facilitate research into the genetic regulation of the sexual development of other organisms. Furthermore, it highlights conserved candidate genes that may underlie the sexually-dimorphic manifestation of different human diseases.

neuroscience↗

bioRxiv2023

Integration of spatially opposing cues by a single interneuron guides decision making in C. elegans

The capacity of animals to integrate and respond to multiple hazardous stimuli in the surroundings is crucial for their survival. In mammals, complex evaluations of the environment require large numbers and different subtypes of neurons. The nematode C. elegans avoid hazardous chemicals they encounter by reversing their direction of movement. How does the worms compact nervous system processes the spatial information and directs the change of motion? We show here that a single interneuron, AVA, receives glutamatergic excitatory signals from head sensory neurons and glutamatergic inhibitory signals from the tail sensory neurons. AVA integrates the spatially distinct and opposing cues, whose output instructs the animals behavioral decision. We further find that the differential activation of AVA from the head and tail stems from distinct anatomical localization of inhibitory and excitatory glutamate-gated receptors along the AVA process, and from different threshold sensitivities of the sensory neurons to aversive stimuli. Our results thus uncover a cellular mechanism that mediates spatial computation of nociceptive cues for efficient decision-making in C. elegans.

neuroscience↗

bioRxiv2022

Sexually dimorphic architecture and function of a mechanosensory circuit in C. elegans

How sensory perception is processed by the two sexes of an organism is still only partially understood. Despite some evidence for sexual dimorphism in auditory and olfactory perception, whether touch is sensed in a dimorphic manner has not been addressed. Here we find that the neuronal circuit for tail mechanosensation in C. elegans is wired differently in the two sexes and employs a different combination of sex-shared sensory neurons and interneurons in each sex. Reverse genetic screens uncovered cell- and sex-specific functions of the alpha-tubulin mec-12 and the sodium channel tmc-1 in sensory neurons, and of the glutamate receptors nmr-1 and glr-1 in interneurons, revealing the underlying molecular mechanisms that mediate tail mechanosensation. Moreover, we show that only in males, the sex-shared interneuron AVG is strongly activated by tail mechanical stimulation, and accordingly is crucial for their behavioral response. Importantly, sex reversal experiments demonstrate that the sexual identity of AVG determines both the behavioral output of the mechanosensory response and the molecular pathways controlling it. Our results present for the first time extensive sexual dimorphism in a mechanosensory circuit at both the cellular and molecular levels.

neuroscience↗

bioRxiv2021

Sex-specific topology of the nociceptive circuit shapes dimorphic behavior in C. elegans

How sexually dimorphic behavior is encoded in the nervous system is poorly understood. Here, we characterize the dimorphic nociceptive behavior in C. elegans and study the underlying circuits, which are composed of the same neurons but are wired differently. We show that while sensory transduction is similar in the two sexes, the downstream network topology markedly shapes behavior. We fit a network model that replicates the observed dimorphic behavior in response to external stimuli, and use it to predict simple network rewirings that would switch the behavior between the sexes. We then show experimentally that these subtle synaptic rewirings indeed flip behavior. Strikingly, 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.

neuroscience↗

bioRxiv2016

Sexually dimorphic differentiation of a C. elegans hub neuron is cell-autonomously controlled by a conserved transcription factor

Functional and anatomical sexual dimorphisms in the brain are either the result of cells that are generated only in one sex, or a manifestation of sex-specific differentiation of neurons present in both sexes. The PHC neurons of the nematode C. elegans differentiate in a strikingly sex-specific manner. While in hermaphrodites the PHC neurons display a canonical pattern of synaptic connectivity similar to that of other sensory neurons, PHC differentiates into a densely connected hub sensory/interneuron in males, integrating a large number of male-specific synaptic inputs and conveying them to both male-specific and sex-shared circuitry. We describe that the differentiation into such a hub neuron involves the sex-specific scaling of several components of the synaptic vesicle machinery, including the vesicular glutamate transporter eat-4/VGLUT, induction of neuropeptide expression, changes in axonal projection morphology and a switch in neuronal function. We demonstrate that these molecular and anatomical remodeling events are controlled cell-autonomously by the phylogenetically conserved Doublesex homolog dmd-3, which is both required and sufficient for sex-specific PHC differentiation. Cellular specificity of dmd-3 action is ensured by its collaboration with non-sex specific terminal selector-type transcription factors whereas sex-specificity of dmd-3 action is ensured by the hermaphrodite-specific master regulator of hermaphroditic cell identity, the Gli-like transcription factor tra-1, which transcriptionally represses dmd-3 in hermaphrodite PHC. Taken together, our studies provide mechanistic insights into how neurons are specified in a sexually dimorphic manner.

neuroscience↗