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Neuronal Nrf/SKN-1B controls a sexually dimorphic neuroendocrine pathway for C. elegans exploratory behaviour

ABSTRACT: The SKN-1/Nrf transcription factor family is integral to metabolic homeostasis. There are three SKN-1 isoforms in Caenorhabditis elegans, each with different functions. One of these, SKN-1B, is expressed specifically in neurons and controls hermaphrodite behaviour in response to food. In a laboratory environment C. elegans hermaphrodites must allocate energy efficiently between exploratory food-seeking behaviour, reproduction, and survival, whereas males have to balance both food-seeking with mate-seeking exploratory behaviours. Here, we evaluate the role of SKN-1B in male behaviour and show that SKN-1B acts in a sexually dimorphic manner to control exploratory behaviour, mitochondrial morphology, and mitochondrial function. Moreover, we show that SKN-1B is expressed in a sexually dimorphic pattern, and that SKN-1B influences gene expression on a much broader scale in males compared to hermaphrodites. This analysis identified a neuronal signalling pathway, specifically in males between SKN-1B, the TGF-β ligand DAF-7 and the chemosensory regulator ODR-10, and that this pathway contributes to increased exploratory behaviour in skn-1b mutant males. Taken together our findings identify SKN-1B as a sex-specific neuronal switch to control food searching and mating behaviours. Sexual dimorphism is essential for optimizing survival and reproductive success and our findings establish SKN-1B as a regulator of sex-specific behavioural and metabolic traits. This work provides new insights into neuronal regulation of metabolism and behaviour, with implications for sex-specific physiological adaptations in other species.

ORGANISM(S): Caenorhabditis elegans

PROVIDER: GSE341296 | GEO | 2026/08/10

REPOSITORIES: GEO

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Project description:Background - One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and the genes that regulate chromatin. AT-Rich Interactive Domain 1B (ARID1B), a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. Methods - A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioural and tran¬scriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioural testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviours, seizure susceptibility and general milestones delays. Results – We validated decreased Arid1b mRNA and protein in Arid1b+/- mice, with signatures of increased axonal and synaptic gene expression and decreased transcriptional regulator and RNA processing expression in adult Arid1b+/- cerebellum. During neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex dependence was observed throughout development; males had an early emergence of this neuroanatomical phenotype at postnatal day 7, whereas females had a delayed emergence around postnatal day 40. Behaviourally, as adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. Brains of adult Arid1b+/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. These results stand in contrast to previously reported data highlighting losses in corpus callosum volume in mice. Limitations – The behaviour and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioural findings, and the transcriptomic analyses was exploratory, with no validation of altered expression beyond Arid1b. Conclusions – This study represents a full validation and investigation of a novel model of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

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Neuronal Nrf/SKN-1B controls a sexually dimorphic neuroendocrine pathway for C. elegans exploratory behaviour

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