Biology subjects

Nurrish, S.

Publications and source records attributed to Nurrish, S..

9 recordsLinked to original sources

bioRxiv2026

Neuron-intrinsic and glial pathways regulate sensory cilia regeneration in adult C. elegans

Primary cilia are microtubule-based organelles that mediate cellular responses to environmental cues. Although cilia disassemble and reassemble upon cell cycle entry and exit, respectively, in dividing cells, it remains unclear whether postmitotic cells such as neurons can regenerate these structures in vivo following injury to restore function, and whether this process recapitulates developmental ciliogenesis. Here we show that a subset of sensory neuron cilia in adult C. elegans regrows following conditional truncation and restores neuronal functions. This regeneration is regulated by both cell-intrinsic and extrinsic mechanisms that are in part distinct from those employed during embryonic ciliogenesis. We find that the conserved ciliogenic DAF-19 RFX transcription factor is dispensable for cilia maintenance in the adult but is required for regeneration, in part via transcriptional upregulation of a subset of ciliary intraflagellar transport (IFT) genes. We further identify the DLK-1 dual leucine-zipper kinase and the CEBP-1 C/EBP transcription factor, previously implicated in axon regeneration, as necessary for efficient cilia regrowth but not for developmental ciliogenesis. We show that cebp-1 expression is induced during cilia truncation and regrowth and that this induction is also DAF-19-dependent. Finally, we show that cilia truncation and regeneration dynamics vary in a neuron type-specific manner and are modulated by signals from surrounding glia. Our results establish that the cilia of mature neurons can regenerate and recover functions in vivo and identify conserved pathways that regulate this process in adult animals.

cell biology↗

bioRxiv2026

Activity induced GEM-4/Copine expression inhibits gap junctions and promotes thermosensory plasticity

Activity induced gene expression promotes behavioral plasticity (including several forms of learning and memory) by altering synaptic connectivity and neuron excitability. While several transcriptional targets modify synapses, little is known about targets regulating excitability. Here, we identify a single MEF-2 and CRH-1/CREB transcriptional target, gem-4/Copine, whose expression increases the excitability of C. elegans body muscles. In muscles, gem-4 expression is repressed by MEF-2 and is induced by CRH-1. GEM-4 expression in muscles decreases the number of gap junctions, thereby increasing membrane resistance and excitability. These results identify activity induced copine expression as a mechanism to control gap junction coupling and excitability.

neuroscience↗

bioRxiv2025

Immature C. elegans motor neurons control early embryo behavior via both synaptic and non-synaptic GABA release

Pre-natal brain activity has long lasting effects on subsequent neurodevelopment. It is unclear if early brain activity is dominated by cell intrinsic, synaptic, or non-synaptic mechanisms. We address this question by analyzing C. elegans embryo behavior in snf-11 mutants, which lack a plasma membrane GABA re-uptake pump (orthologous to GAT1). At 510-570 minutes post-fertilization, embryo motion was transiently and potently inhibited in snf-11 GAT1 mutants, which precedes formation of most nerve ring synapses. This transient motion inhibition requires GABA synthesis in DD motor neurons and UNC-49 GABAA receptors in body muscles. When motion inhibition occurs, DD neurons have not yet completed neurite outgrowth. Genetic analysis suggests that motion inhibition was mediated by both synaptic and tonic GABA release from DD motor neurons. These results suggest that DD neurons control embryo behavior prior to completing their developmental maturation. Significance StatementLittle is known about how prenatal circuits control embryo behavior. We show that the motion of early C. elegans embryos is transiently inhibited by immature GABAergic motor neurons that have not yet completed neurite outgrowth. GABAs inhibitory effect on early embryo behavior occurs before most synapses have formed in the worms central neuropil. For this early behavior, we find that synaptic GABA release plays a minor role while non-synaptic mechanisms predominate. Our results suggest that non-synaptic forms of GABA transmission play a significant role in prenatal circuits.

neuroscience↗

bioRxiv2025

Experience-dependent reconfiguration of receptors at a sensory compartment regulates neuronal plasticity

Neurons continuously adjust their properties as a function of experience. Precise modulation of neuronal responses is achieved by multiple cellular mechanisms that operate over a range of timescales. Primary sensory neurons rapidly adapt their sensitivities via posttranslational mechanisms including regulated trafficking of sensory molecules1-4 but also alter their transcriptional profiles on longer timescales to adapt to persistent sensory stimuli5-8. How diverse transcriptional and posttranscriptional pathways are coordinated in individual sensory neurons to accurately adjust their functions and drive behavioral plasticity is unclear. Here we show that temperature experience modulates both transcription and trafficking of thermoreceptors on different timescales in the C. elegans AFD thermosensory neurons to regulate response plasticity. Expression of the PY motif-containing adaptor protein (PYT-1) as well as the GCY-18 warm temperature-responsive guanylyl cyclase thermoreceptor9 is transcriptionally upregulated in AFD upon a temperature upshift5,10. We find that as GCY-18 begins to accumulate at the AFD sensory endings, the GCY-23 cooler temperature-responsive thermoreceptor9 exhibits altered subcellular localization and increased retrograde trafficking, thereby increasing the functional GCY-18 to GCY-23 ratio in the AFD sensory compartment. Altered GCY-23 localization and trafficking requires PYT-1-dependent endocytosis, and we show that PYT-1-mediated modulation of the GCY-18 to GCY-23 protein ratio at the AFD sensory endings is necessary to shift the AFD response threshold towards warmer values following the temperature upshift. Our results describe a mechanism by which transcriptional and posttranscriptional mechanisms are temporally coordinated across sensory receptors to fine tune experience-dependent plasticity in the response of a single sensory neuron type.

neuroscience↗

bioRxiv2025

A lateralized sensory signaling pathway mediates context-dependent olfactory plasticity in C. elegans

Lateralization of neuronal functions plays a critical role in regulating behavioral flexibility, but the underlying molecular mechanisms are challenging to establish at a single-neuron level. We previously showed that attraction of C. elegans to a medium-chain alcohol switches to avoidance in a uniform background of a second attractive odorant. This context-dependent behavioral plasticity is mediated by symmetric inversion of the odor-evoked response sign in the bilateral AWC olfactory neurons. Here we show that this symmetric response plasticity is driven by asymmetric molecular mechanisms in the AWC neuron pair. Mutations in the gcy-12 receptor guanylyl cyclase abolish odor response plasticity only in AWCOFF; the opposing odor-evoked response signs in AWCOFF and AWCON in gcy-12 mutants results in these animals being behaviorally indifferent to this chemical. We find that gcy-12 is expressed, and required, in both AWC neurons to regulate odor response plasticity only in AWCOFF. We further show that disruption of AWC fate lateralization results in loss of asymmetry in the response plasticity in gcy-12 mutants. Our results indicate that symmetric neuronal response plasticity can arise from asymmetry in underlying molecular mechanisms, and suggest that lateralization of signaling pathways in defined conditions may enhance neuronal and behavioral flexibility.

neuroscience↗

bioRxiv2022

CASK and FARP coordinately control pre- and post-synaptic function

Changes in neurotransmitter receptor abundance at post-synaptic elements play a pivotal role in regulating synaptic strength. For this reason, there is significant interest in identifying and characterizing the scaffolds required for receptor localization at different synapses. Here we analyze the role of two C. elegans post-synaptic scaffolding proteins (LIN-2/CASK and FRM-3/FARP) at cholinergic neuromuscular junctions. Constitutive knockouts or muscle specific inactivation of lin-2 and frm-3 dramatically reduced spontaneous and evoked post-synaptic currents. These synaptic defects resulted from the decreased abundance of two classes of post-synaptic ionotropic acetylcholine receptors (ACR-16/CHRNA7 and levamisole-activated AChRs). LIN-2s AChR scaffolding function is mediated by its SH3 and PDZ domains, which interact with AChRs and FRM-3/FARP, respectively. Thus, our findings show that post-synaptic LIN-2/FRM-3 complexes promote cholinergic synaptic transmission by recruiting AChRs to post-synaptic elements.

neuroscience↗

bioRxiv2021

Systematic analysis of C. elegans embryo behavior reveals a stereotyped developmental progression and a rhythmic pattern of behavioral quiescence

AO_SCPLOWBSTRACTC_SCPLOWSystematic analysis of rich behavioral recordings is being used to uncover how circuits encode complex behaviors. Here we apply this approach to embryos. What are the first embryonic behaviors and how do they evolve as early neurodevelopment ensues? To address these questions, we present a systematic description of behavioral maturation for Caenorhabditis elegans embryos. Posture libraries were built using a genetically encoded motion capture suit imaged with light-sheet microscopy and annotated using custom tracking software. Analysis of cell trajectories, postures, and behavioral motifs revealed a stereotyped developmental progression. Early movement is dominated by flipping between dorsal and ventral coiling, which gradually slows into a period of reduced motility. Late-stage embryos exhibit sinusoidal waves of dorsoventral bends, prolonged bouts of directed motion, and a rhythmic pattern of pausing, which we designate slow wave twitch (SWT). Synaptic transmission is required for late-stage motion but not for early flipping nor the intervening inactive phase. A high-throughput behavioral assay and calcium imaging revealed that SWT is elicited by the rhythmic activity of a quiescence-promoting neuron (RIS). Similar periodic quiescent states are seen prenatally in diverse animals and may play an important role in promoting normal developmental outcomes.

neuroscience↗

bioRxiv2021

Shank promotes action potential repolarization by recruiting BK channels to calcium nanodomains

Mutations altering the scaffolding protein Shank are linked to several psychiatric disorders, and to synaptic and behavioral defects in mice. Among its many binding partners, Shank directly binds CaV1 voltage activated calcium channels. Here we show that the C. elegans SHN-1/Shank promotes CaV1 coupling to calcium activated potassium channels. Mutations inactivating SHN-1, and those preventing SHN-1 binding to EGL-19/CaV1 all increase action potential durations in body muscles. Action potential repolarization is mediated by two classes of potassium channels: SHK-1/KCNA and SLO-1 and SLO-2 BK channels. BK channels are calcium-dependent, and their activation requires tight coupling to EGL-19/CaV1 channels. SHN-1s effects on AP duration are mediated by changes in BK channels. In shn-1 mutants, SLO-2 currents and channel clustering are significantly decreased in both body muscles and neurons. Finally, increased and decreased shn-1 gene copy number produce similar changes in AP width and SLO-2 current. Collectively, these results suggest that an important function of Shank is to promote nanodomain coupling of BK with CaV1.

neuroscience↗

bioRxiv2020

Caenorhabditis elegans junctophilin has tissue-specific functions and regulates neurotransmission with extended-synaptotagmin

The junctophilin family of proteins tether together plasma membrane (PM) and endoplasmic reticulum (ER) membranes, and couple PM- and ER-localized calcium channels. Understanding in vivo functions of junctophilins is of great interest for dissecting the physiological roles of ER-PM contact sites. Here, we show that the sole C. elegans junctophilin JPH-1 localizes to discrete membrane contact sites in neurons and muscles and has important tissue-specific functions. jph-1 null mutants display slow growth and development due to weaker contraction of pharyngeal muscles, leading to reduced feeding. In the body wall muscle, JPH-1 co-localizes with the PM-localized EGL-19 voltage-gated calcium channel and ER-localized UNC-68/RyR calcium channel, and is required for animal movement. We also find an unexpected cell non-autonomous effect of jph-1 in axon regrowth after injury. In neurons, JPH-1 co-localizes with the membrane contact site protein Extended-SYnaptoTagmin 2 (ESYT-2) and modulates neurotransmission. Interestingly, jph-1 and esyt-2 null mutants display mutual suppression in their response to aldicarb, suggesting that JPH-1 and ESYT-1 have antagonistic roles in neuromuscular synaptic transmission. Our genetic double mutant analysis also reveals that jph-1 functions in overlapping pathways with two PM-localized voltage-gated calcium channels, egl-19 and unc-2, and unc-68/RyR for animal health and development. Finally, we show that unc-68/RyR is required for JPH-1 localization to ER-PM puncta. Our data demonstrate important roles for junctophilin in cellular physiology, and also provide insights into how junctophilin functions together with other calcium channels in vivo.

genetics↗