De Bono M et al. (2002) Nature "Social feeding in Caenorhabditis elegans is induced by neurons that detect aversive stimuli."

Tobin DM, De Bono M, Davis MW, Bargmann CI, Avery L

[Nature, 2002]

Natural Caenorhabditis elegans isolates exhibit either social or solitary feeding on bacteria. We show here that social feeding is induced by nociceptive neurons that detect adverse or stressful conditions. Ablation of the nociceptive neurons ASH and ADL transforms social animals into solitary feeders. Social feeding is probably due to the sensation of noxious chemicals by ASH and ADL neurons; it requires the genes ocr-2 and osm-9, which encode TRP-related transduction channels, and odr-4 and odr-8, which are required to localize sensory chemoreceptors to cilia. Other sensory neurons may suppress social feeding, as social feeding in ocr-2 and odr-4 mutants is restored by mutations in osm-3, a gene required for the development of 26 ciliated sensory neurons. Our data suggest a model for regulation of social feeding by opposing sensory inputs: aversive inputs to nociceptive neurons promote social feeding, whereas antagonistic inputs from neurons that express osm-3 inhibit aggregation.

De Bono M et al. (1996) Genetics "Evolution of sex determination in caenorhabditis: unusually high divergence of tra-1 and its functional consequences."

Hodgkin JA, De Bono M

[Genetics, 1996]

The tra-1 gene is a terminal regulator of somatic sex in Caenorhabditis elegans: high tra-1 activity elicits female development, low tra-1 activity elicits male development. To investigate the function and evolution of tra-1, we examined the tra-1 gene from the closely related nematode C. briggsae. Ce-tra-1 and Cb-tra-1 are unusually divergent. Each gene generates two transcripts, but only one of these is present in both species. This common transcript encodes TRA-1A, which shows only 44% amino acid identity between the species, a figure much lower than that for previously compared genes. A Cb-tra-1 transgene rescues many tissues of tra-1(null) mutants of C. elegans but not the somatic gonad or germ line. This transgene also causes nongonadal feminization of XO animals, indicating incorrect sexual regulation. Alignment of Ce-TRA-1A and Cb-TRA-1A defines several conserved regions likely to be important for tra-1 function. The phenotypic differences between Ce-tra-1(null) mutants rescued by Cb-tra-1 transgenes and wild-type C. elegans indicate significant divergence of regulatory regions. These molecular and functional studies suggest that evolution of sex determination in nematodes is rapid and genetically complex.

De Bono M et al. (1998) Cell "Natural variation in a neuropeptide Y receptor homolog modifies social behavior and food response in C. elegans."

Bargmann CI, De Bono M

[Cell, 1998]

Natural isolates of C. elegans exhibit either solitary or social feeding behavior. Solitary foragers move slowly on a bacterial lawn and disperse across it, while social foragers move rapidly on bacteria and aggregate together. A loss-of-function mutation in the npr-1 gene, which encodes a predicted G protein-coupled receptor similar to neuropeptide Y receptors, causes a solitary strain to take on social behavior. Two isoforms of NPR-1 that differ at a single residue occur in the wild. One isoform, NPR-1 215F, is found exclusively in social strains, while the other isoform, NPR-1 215V, is found exclusively in solitary strains. An NPR-1 215V transgene can induce solitary feeding behavior in a wild social strain. Thus, isoforms of a putative neuropeptide receptor generate natural variation in C. elegans feeding behavior.AD - Howard Hughes Medical Institute, Department of Anatomy, The University of California, San Francisco 94143-0452, USA.FAU - de Bono, MAU - de Bono MFAU - Bargmann, C IAU - Bargmann CILA - engSI - GENBANK/U49944PT - Journal ArticleCY - UNITED STATESTA - CellJID - 0413066RN - 0 (Helminth Proteins)RN - 0 (Receptors, Neuropeptide Y)RN - EC 3.6.1.- (GTP-Binding Proteins)SB - IM

de Bono M et al. (1995) Genes Dev "Dominant feminizing mutations implicate protein-protein interactions as the main mode of regulation of the nematode sex-determining gene tra-1."

Hodgkin JA, De Bono M, Zarkower D

[Genes Dev, 1995]

The tra-1 gene is the terminal global selector of somatic sex in Caenorhabditis elegans: High tra-1 activity elicits female somatic development while low tra-1 activity elicits male development. Previous genetic studies defined a cascade of negatively interacting genes that regulates tra-1 activity in response to the primary sex-determining signal. Here, we investigate the last step in this regulatory cascade, by studying rare gain-of-function (gf) mutations of tra-1 that direct female somatic development irrespective of the upstream sex-determining signal. These mutations appear to abolish negative regulation of tra-1 in male tissues. We identify the lesions associated with 29 of these mutations and find that all affect a short stretch of amino acid residues present in both protein products of the tra-1 gene. Twenty-six alleles are associated with single nonconservative amino acid substitutions. Two alleles affect tra-1 RNA splicing and generate messages that omit part or all of the exon encoding this short stretch. These results suggest that sexual regulation of tra-1 is achieved post-translationally, by an inhibitory protein-protein interaction. The amino acid stretch altered by the tra-1(gf) mutations may define a site of interaction for negative regulators of tra-1. The stretch includes a potential phosphorylation site for glycogen synthase kinase 3 and may be conserved in the human gene GLI3, a homolog of tra-1 identified previously.

Kubiak TM et al. (2003) J Biol Chem "Differential activation of "social" and "solitary" variants of the Caenorhabditis elegans G protein-coupled receptor NPR-1 by its cognate ligand AF9."

Larsen MJ, Nulf SC, Bowman JW, Lowery DE, Zantello MR, Burton KJ, Modric T, Kubiak TM

[J Biol Chem, 2003]

Natural variations of wild Caenorhabditis elegans isolates having either Phe-215 or Val-215 in NPR-1, a putative orphan neuropeptide Y-like G protein-coupled receptor, result in either "social" or "solitary" feeding behaviors ( de Bono, M., and Bargmann, C. I. ( 1998) Cell 94, 679 - 689). We identified a nematode peptide, GLGPR-PLRF-NH2 (AF9), as a ligand activating the cloned NPR-1 receptor heterologously expressed in mammalian cells. Shifting cell culture temperatures from 37 to 28 degreesC, implemented 24 h after transfections, was essential for detectable functional expression of NPR-1. AF9 treatments linked both cloned receptor variants to activation of Gi/Go proteins and cAMP inhibition, thus allowing for classification of NPR-1 as an inhibitory G protein-coupled receptor. The Val-215 receptor isoform displayed higher binding and functional activity than its Phe-215 counterpart. This finding parallels the in vivo observation of a more potent repression of social feeding by the npr-1 gene encoding the Val-215 form of the receptor, resulting in dispersing ( solitary) animals. Since neuropeptide Y shows no sequence homology to AF9 and was functionally inactive at the cloned NPR-1, we propose to rename NPR-1 and refer to it as an AF9 receptor, AF9-R1.

Coates JC et al. (2002) Nature "Antagonistic pathways in neurons exposed to body fluid regulate social feeding in Caenorhabditis elegans."

De Bono M, Coates JC

[Nature, 2002]

Wild isolates of Caenorhabditis elegans can feed either alone or in groups(1,2). This natural variation in behaviour is associated with a single residue difference in NPR-1, a predicted G-protein-coupled neuropeptide receptor related to Neuropeptide Y receptors(2). Here we show that the NPR-1 isoform associated with solitary feeding acts in neurons exposed to the body fluid to inhibit social feeding. Furthermore, suppressing the activity of these neurons, called AQR, PQR and URX, using an activated K+ channel, inhibits social feeding. NPR-1 activity in AQR, PQR and URX neurons seems to suppress social feeding by antagonizing signalling through a cyclic GMP-gated ion channel encoded by tax-2 and tax-4. We show that mutations in tax-2 or tax-4 disrupt social feeding, and that tax-4 is required in several neurons for social feeding, including one or more of AQR, PQR and URX. The AQR, PQR and URX neurons are unusual in C. elegans because they are directly exposed to the pseudocoelomic body fluid(3). Our data suggest a model in which these neurons integrate antagonistic signals to control the choice between social and solitary feeding behaviour.

Fenk LA et al. (2017) Proc Natl Acad Sci U S A "Memory of recent oxygen experience switches pheromone valence in Caenorhabditis elegans."

Fenk LA, De Bono M

[Proc Natl Acad Sci U S A, 2017]

Animals adjust their behavioral priorities according to momentary needs and prior experience. We show that Caenorhabditis elegans changes how it processes sensory information according to the oxygen environment it experienced recently. C. elegans acclimated to 7% O2 are aroused by CO2 and repelled by pheromones that attract animals acclimated to 21% O2 This behavioral plasticity arises from prolonged activity differences in a circuit that continuously signals O2 levels. A sustained change in the activity of O2-sensing neurons reprograms the properties of their postsynaptic partners, the RMG hub interneurons. RMG is gap-junctionally coupled to the ASK and ADL pheromone sensors that respectively drive pheromone attraction and repulsion. Prior O2 experience has opposite effects on the pheromone responsiveness of these neurons. These circuit changes provide a physiological correlate of altered pheromone valence. Our results suggest C. elegans stores a memory of recent O2 experience in the RMG circuit and illustrate how a circuit is flexibly sculpted to guide behavioral decisions in a context-dependent manner.

Fenk LA et al. (2015) Proc Natl Acad Sci U S A "Environmental CO2 inhibits Caenorhabditis elegans egg-laying by modulating olfactory neurons and evokes widespread changes in neural activity."

De Bono M, Fenk LA

[Proc Natl Acad Sci U S A, 2015]

Carbon dioxide (CO2) gradients are ubiquitous and provide animals with information about their environment, such as the potential presence of prey or predators. The nematode Caenorhabditis elegans avoids elevated CO2, and previous work identified three neuron pairs called "BAG," "AFD," and "ASE" that respond to CO2 stimuli. Using in vivo Ca(2+) imaging and behavioral analysis, we show that C. elegans can detect CO2 independently of these sensory pathways. Many of the C. elegans sensory neurons we examined, including the AWC olfactory neurons, the ASJ and ASK gustatory neurons, and the ASH and ADL nociceptors, respond to a rise in CO2 with a rise in Ca(2+). In contrast, glial sheath cells harboring the sensory endings of C. elegans' major chemosensory neurons exhibit strong and sustained decreases in Ca(2+) in response to high CO2. Some of these CO2 responses appear to be cell intrinsic. Worms therefore may couple detection of CO2 to that of other cues at the earliest stages of sensory processing. We show that C. elegans persistently suppresses oviposition at high CO2. Hermaphrodite-specific neurons (HSNs), the executive neurons driving egg-laying, are tonically inhibited when CO2 is elevated. CO2 modulates the egg-laying system partly through the AWC olfactory neurons: High CO2 tonically activates AWC by a cGMP-dependent mechanism, and AWC output inhibits the HSNs. Our work shows that CO2 is a more complex sensory cue for C. elegans than previously thought, both in terms of behavior and neural circuitry.

Olofsson B et al. (2008) Curr Biol "Sleep: dozy worms and sleepy flies."

Olofsson B, De Bono M

[Curr Biol, 2008]

Recent work on quiescent states in Caenorhabditis elegans suggests that worms exhibit behaviours reminiscent of satiety and sleep in mammals. At a molecular level, signalling through the EGF receptor and protein kinase G promotes quiescent states in both worms and flies, suggesting conserved mechanisms for sleep-like behaviours.

Valperga G et al. (2022) Elife "Impairing one sensory modality enhances another by reconfiguring peptidergic signalling in Caenorhabditis elegans."

De Bono M, Valperga G

[Elife, 2022]

Animals that lose one sensory modality often show augmented responses to other sensory inputs. The mechanisms underpinning this cross-modal plasticity are poorly understood. We probe such mechanisms by performing a forward genetic screen for mutants with enhanced O₂ perception in <i>Caenorhabditis elegans</i>. Multiple mutants exhibiting increased O₂ responsiveness concomitantly show defects in other sensory responses. One mutant, <i>qui-1</i>, defective in a conserved NACHT/WD40 protein, abolishes pheromone-evoked Ca²⁺ responses in the ADL pheromone-sensing neurons. At the same time, ADL responsiveness to pre-synaptic input from O₂-sensing neurons is heightened in <i>qui-1</i>, and other sensory defective mutants, resulting in enhanced neurosecretion although not increased Ca²⁺ responses. Expressing <i>qui-1</i> selectively in ADL rescues both the <i>qui-1</i> ADL neurosecretory phenotype and enhanced escape from 21% O₂. Profiling ADL neurons in <i>qui-1</i> mutants highlights extensive changes in gene expression, notably of many neuropeptide receptors. We show that elevated ADL expression of the conserved neuropeptide receptor NPR-22 is necessary for enhanced ADL neurosecretion in <i>qui-1</i> mutants, and is sufficient to confer increased ADL neurosecretion in control animals. Sensory loss can thus confer cross-modal plasticity by changing the peptidergic connectome.