Biology subjects

Schroeder, F. C.

Publications and source records attributed to Schroeder, F. C..

33 records · Page 2Linked to original sources

bioRxiv2022

Sex-specificity of the C. elegans metabolome

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 a series of germline 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, 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 provides a blueprint for the discovery of sex-dependent metabolites in other animals.

bioinformatics↗

bioRxiv2022

D-2-Hydroxyglutarate dehydrogenase connects the propionate shunt to ketone body metabolism in Caenorhabditis elegans

In humans, mutations in D-2-hydroxyglutarate (D-2HG) dehydrogenase (D2HGDH) result in D-2HG accumulation, delayed development, seizures, and ataxia. While the mechanisms of 2HG-associated diseases have been studied extensively, the endogenous metabolism of D-2HG remains unclear in any organism. Here, we find that, in Caenorhabditis elegans, D-2HG is produced in the propionate shunt, which is transcriptionally activated when flux through the canonical, vitamin B12-dependent propionate breakdown pathway is perturbed. Deletion of the D2HGDH ortholog, dhgd-1, results in embryonic lethality, mitochondrial defects, and the upregulation of ketone body metabolism genes. Viability can be rescued by RNAi of hphd-1, which encodes the enzyme that produces D-2HG, or by supplementing either vitamin B12 or the ketone body 3-hydroxybutyrate (3HB). Altogether, our findings support a model in which C. elegans relies on ketone bodies for energy when vitamin B12 levels are low, and in which a loss of dhgd-1 causes lethality by limiting ketone body production. HIGHLIGHTS- D-2-hydroxyglutarate is produced by HPHD-1 in the propionate shunt pathway - DHGD-1 recycles 2-hydroxyglutarate to sustain flux through the propionate shunt - dhgd-1 loss perturbs ketone body metabolism and causes embryonic lethality - 3-Hydroxybutyrate, vitamin B12 or hphd-1 RNAi rescue dhgd-1 mutant lethality

biochemistry↗

bioRxiv2021

Comparative metabolomics with Metaboseek reveals functions of a conserved fat metabolism pathway in C. elegans

Untargeted metabolomics via high-resolution mass spectrometry (HRMS) can reveal more than 100,000 molecular features in a single sample, many of which may represent unidentified metabolites, posing significant challenges to data analysis. We here introduce Metaboseek, an open-source analysis platform designed for untargeted comparative metabolomics and demonstrate its utility by uncovering biosynthetic functions of a conserved fat metabolism pathway, -oxidation, using C. elegans as a model. Metaboseek integrates modules for molecular feature detection, statistics, molecular formula prediction, and fragmentation (MS/MS) analysis, which uncovered more than 200 previously uncharacterized -oxidation-dependent metabolites in an untargeted comparison of wildtype and -oxidation-defective hacl-1 mutants. The identified metabolites support the predicted enzymatic function of HACL-1 and revealed that -oxidation participates in metabolism of endogenous {beta}-methyl-branched fatty acids and food-derived cyclopropane lipids. Our results showcase compound discovery and feature annotation at scale via untargeted comparative metabolomics applied to a conserved primary metabolic pathway and suggest a model for the metabolism of cyclopropane lipids.

biochemistry↗

bioRxiv2020

Modular metabolite assembly in C. elegans lysosome-related organelles

Signaling molecules derived from attachment of diverse metabolic building blocks to ascarosides play a central role in the life history of C. elegans and other nematodes; however, many aspects of their biogenesis remain unclear. Using comparative metabolomics, we show that a pathway mediating formation of intestinal lysosome-related organelles (LROs) is required for biosynthesis of most modular ascarosides as well as previously undescribed modular glucosides. Similar to modular ascarosides, the modular glucosides are derived from highly selective assembly of moieties from nucleoside, amino acid, neurotransmitter, and lipid metabolism, suggesting that modular glucosides, like the ascarosides, may serve signaling functions. We further show that carboxylesterases that localize to intestinal organelles are required for the assembly of both modular ascarosides and glucosides via ester and amide linkages. Further exploration of LRO function and carboxylesterase homologs in C. elegans and other animals may reveal additional new compound families and signaling paradigms. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=158 SRC="FIGDIR/small/262956v2_ufig1.gif" ALT="Figure 1"> View larger version (42K): org.highwire.dtl.DTLVardef@6e83cborg.highwire.dtl.DTLVardef@18e9302org.highwire.dtl.DTLVardef@1557670org.highwire.dtl.DTLVardef@1d2ca50_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2020

Dual-purpose isocyanides produced by Aspergillus fumigatus contribute to cellular copper sufficiency and exhibit antimicrobial activity

The maintenance of sufficient but non-toxic pools of metal micronutrients is accomplished through diverse homeostasis mechanisms in fungi. Siderophores play a well-established role for iron homeostasis; however, no copper-binding analogs have been found in fungi. Here we demonstrate that in Aspergillus fumigatus isocyanides derived from the xan biosynthetic gene cluster (BGC) bind copper, impact cellular copper content, and have significant metal-dependent antimicrobial properties. xan BGC-derived isocyanides are secreted and bind copper as visualized by a chrome azurol S (CAS) assay and inductively coupled plasma-mass spectrometry (ICP-MS) analysis of A. fumigatus intracellular copper pools demonstrated a role for xan cluster metabolites in the accumulation of copper. A. fumigatus coculture with A. nidulans, Candida albicans and a variety of pathogenic bacteria establish copper-dependent antimicrobial properties of xan BGC metabolites including inhibition of laccase activity. Similarly, inhibition of Pseudomonas aeruginosa by low concentrations of the xan isocyanide xanthocillin was copper-dependent. Other metals also reduced xanthocillins antimicrobial properties, but less efficiently than copper. As variations of the xan BGC exist in other filamentous fungi, we suggest that xanthocillin-like natural products represent a first example for fungal small molecules that serve to maintain copper sufficiency and mediate interactions with competing microbes. SignificanceMetal homeostasis is an integral part of metabolism for any organism. A vast array of small molecules are already known to mediate metal homeostasis in fungi and bacteria; however, unlike their bacterial counterparts, to-date there are no known fungal small molecules that function to maintain copper homeostasis. Discovery of copper binding small molecules produced by A. fumigatus gives insight into mechanisms other than the extensively studied copper transporters or metalloproteins for how fungi can regulate copper. This has important ecological implications as securing scarce nutrients is central for fitness and survival. Additionally, studying this mechanism in A. fumigatus provides a basis for investigation of copper regulation pathways in other fungi.

microbiology↗

bioRxiv2020

Inversion of pheromone preference optimizes foraging in C. elegans

Foraging animals have to locate food sources that are usually patchily distributed and subject to competition. Deciding when to leave a food patch is challenging and requires the animal to integrate information about food availability with cues signaling the presence of other individuals (e.g. pheromones). To study how social information transmitted via pheromones can aid foraging decisions, we investigated the behavioral responses of the model nematode Caenorhabditis elegans to food depletion and pheromone accumulation in food patches. We experimentally show that animals consuming a food patch leave it at different times and that the leaving time affects the animal preference for its pheromones. In particular, worms leaving early are attracted to their pheromones, while worms leaving later are repelled by them. We further demonstrate that the inversion from attraction to repulsion depends on associative learning and, by implementing a simple model, we highlight that it is an adaptive solution to optimize food intake during foraging.

ecology↗

bioRxiv2019

Natural diversity in the predatory behavior facilitates the establishment of a new robust model strain for nematode-trapping fungi

Nematode-trapping fungi (NTF) are a group of specialized microbial predators that consume nematodes when food sources are limited. Predation is initiated when conserved nematode ascaroside pheromones are sensed, followed by the development of complex trapping devices. To gain insights into the co-evolution of this inter-kingdom predator-prey relationship, we investigated natural populations of nematodes and NTF, that we found to be ubiquitous in soils. Arthrobotrys species were sympatric with various nematode species and behaved as generalist predators. The ability to sense prey amongst wild isolates of A. oligospora varied greatly, as determined by the number of traps after exposure to Caenorhabditis elegans. While some strains were highly sensitive to C. elegans and the nematode pheromone ascarosides, others responded only weakly. Furthermore, strains that were highly sensitive to the nematode prey also developed traps faster. The polymorphic nature of trap formation correlated with competency in prey killing, as well as with the phylogeny of A. oligospora natural strains, calculated after assembly and annotation of the genomes of twenty isolates. A chromosome level genome assembly and annotation was established for one of the most sensitive wild isolate, and deletion of the only G protein {beta} subunit-encoding gene of A. oligospora nearly abolished trap formation, implicating G protein signaling in predation. In summary, our study establishes a highly responsive A. oligospora wild isolate as a novel model strain for the study of fungal-nematode interactions and demonstrates that trap formation is a fitness character in generalist predators of the NTF family. Significance statementNematode-trapping fungi (NTF) are carnivorous microbes that hold potential to be used as biological control agents due to their ability to consume nematodes. In this work we show that NTF are ubiquitous generalist predators found in sympatry with their prey in soil samples. Wild isolates of NTF displayed a naturally diverse ability to execute their predatory lifestyle. We generated a large whole genome sequencing dataset for many of the fungal isolates that will serve as the basis of future projects isolates. In particular, we establish TWF154, a highly responsive strain of Arthrobotrys oligospora, as a model strain to study the genetics of NTF. Lastly, we provide evidence that G-protein signaling is necessary for trap induction in NTF.

molecular biology↗

bioRxiv2019

Modulation of sensory behavior and food choice by an enteric bacteria-produced neurotransmitter

Animals coexist in commensal, pathogenic or mutualistic relationships with complex communities of diverse organisms including microbes1. Some bacteria produce bioactive neurotransmitters which have been proposed to modulate host nervous system activity and behaviors2. However, the mechanistic basis of this microbiota-brain modulation and its physiological relevance is largely unknown. Here we show that in C. elegans, the neuromodulator tyramine (TA) produced by gut-colonizing commensal Providencia bacteria can bypass the requirement for host TA biosynthesis to manipulate a host sensory decision. Bacterially-produced TA is likely converted to octopamine (OA) by the host tyramine beta-hydroxylase enzyme. OA, in turn, targets the OCTR-1 receptor on the ASH/ASI sensory neurons to modulate an aversive olfactory response. We identify genes required for TA biosynthesis in Providencia, and show that these genes are necessary for modulation of host behavior. We further find that C. elegans colonized by Providencia preferentially select these bacteria in food choice assays, and that this selection bias requires bacterially-produced TA. Our results demonstrate that a neurotransmitter produced by gut microbiota mimics the functions of the cognate host molecule to override host control of a sensory decision, thereby promoting fitness of both host and microbe.

neuroscience↗

bioRxiv2019

Selection and gene flow shape niche-associated copy-number variation of pheromone receptor genes

From quorum sensing in bacteria to pheromone signaling in social insects, chemical communication mediates interactions among individuals in a local population. In Caenorhabditis elegans, ascaroside pheromones can dictate local population density, in which high levels of pheromones inhibit the reproductive maturation of individuals. Little is known about how natural genetic diversity affects the pheromone responses of individuals from diverse habitats. Here, we show that a niche-associated copy-number variation (CNV) of pheromone receptor genes contributes to natural differences in pheromone responses. We found putative loss-of-function deletions that reduce copy number of duplicated pheromone receptor genes (srg-36 and srg-37), which were shown previously to be selected in population-dense laboratory cultures. A common natural deletion in the less functional copy (srg-37) arose from a single ancestral population that spread throughout the world and underlies reduced pheromone sensitivity across the global C. elegans population. This deletion is enriched in wild strains that were isolated from a rotting fruit niche, where proliferating populations are often found. Taken together, these results demonstrate that selection and gene flow together shape the copy number of pheromone receptor genes in natural C. elegans populations to facilitate local adaptation to diverse niches.

evolutionary biology↗

bioRxiv2018

Attraction to pheromones in Caenorhabditis elegans can be reversed through associative learning

Despite the ubiquity and importance of chemical signaling, we have only limited insight about the role of learning in the response to pheromones. Here, we demonstrate that responses to pheromones can be reprogrammed through associative learning. In particular, we show that attraction to ascaroside pheromones in the model nematode Caenorhabditis elegans can be reversed by training the animals to associate either a pheromone blend or single synthetic ascarosides with the lack of food. This behavioral plasticity alters worm preference for pheromones following consumption of a food patch, possibly improving foraging in natural environments. By bridging the gap between the current knowledge on the chemical language and the learning abilities of C. elegans, we provide insight on the possible links between learning and chemical signaling in animals.

ecology↗

bioRxiv2018

Natural variation in arsenic toxicity is explained by differences in branched chain amino acid catabolism

We find that variation in the dbt-1 gene underlies natural differences in Caenorhabditis elegans responses to the toxin arsenic. This gene encodes the E2 subunit of the branched-chain -keto acid dehydrogenase (BCKDH) complex, a core component of branched-chain amino acid (BCAA) metabolism. We causally linked a non-synonymous variant in the conserved lipoyl domain of DBT-1 to differential arsenic responses. Using targeted metabolomics and chemical supplementation, we demonstrate that differences in responses to arsenic are caused by variation in iso-branched chain fatty acids. Additionally, we show that levels of branched chain fatty acids in human cells are perturbed by arsenic treatment. This finding has broad implications for arsenic toxicity and for arsenic-focused chemotherapeutics across human populations. Our study implicates the BCKDH complex and BCAA metabolism in arsenic responses, demonstrating the power of C. elegans natural genetic diversity to identify novel mechanisms by which environmental toxins affect organismal physiology.

genetics↗

bioRxiv2018

Ethylene signaling regulates natural variation in the abundance of antifungal acetylated diferuloylsucroses and Fusarium graminearum resistance in maize seedling roots

O_LIThe production and regulation of defensive specialized metabolites plays a central role in pathogen resistance in maize (Zea mays) and other plants. Therefore, identification of genes involved in plant specialized metabolism can contribute to improved disease resistance.\nC_LIO_LIWe used comparative metabolomics to identify previously unknown antifungal metabolites in maize seedling roots, and investigated the genetic and physiological mechanisms underlying their natural variation using quantitative trait locus (QTL) mapping and comparative transcriptomics approaches.\nC_LIO_LITwo maize metabolites, smilaside A (3,6-diferuloyl-3',6'-diacetylsucrose) and smiglaside C (3,6-diferuloyl-2',3',6'-triacetylsucrose), that may contribute to maize resistance against Fusarium graminearum and other fungal pathogens were identified. Elevated expression of an ethylene receptor gene, ETHYLENE INSENSITIVE 2 (ZmEIN2), co-segregated with decreased smilaside A/smiglaside C ratio. Pharmacological and genetic manipulation of ethylene availability and sensitivity in vivo indicated that, whereas ethylene was required for the production of both metabolites, the smilaside A/smiglaside C ratio was negatively regulated by ethylene sensitivity. This ratio, rather than the absolute abundance of these two metabolites, was important for maize seedling root defense against F. graminearum.\nC_LIO_LIEthylene signaling regulates the relative abundance of the two F. graminearum-resistance-related metabolites and affects resistance against F. graminearum in maize seedling roots.\nC_LI

plant biology↗

bioRxiv2018

Co-option of neurotransmitter signaling for inter-organismal communication in C. elegans

Biogenic amine neurotransmitters play a central role in metazoan biology, and both their chemical structures and cognate receptors are evolutionarily conserved. Their primary roles are in intra-organismal signaling, whereas biogenic amines are not normally recruited for communication between separate individuals. Here, we show that in C. elegans, a neurotransmitter-sensing G protein-coupled receptor, TYRA-2, is required for avoidance responses to osas#9, an ascaroside pheromone that incorporates the neurotransmitter octopamine. Neuronal ablation, cell-specific genetic rescue, and calcium imaging show that tyra-2 expression in the nociceptive neuron ASH is necessary and sufficient to induce osas#9 avoidance. Ectopic expression in the AWA neuron, which is generally associated with attractive responses, reverses the response to osas#9, resulting in attraction instead of avoidance behavior, confirming that TYRA-2 partakes in sensing osas#9. The TYRA-2/osas#9 signaling system thus represents an inter-organismal communication channel that evolved via co-option of a neurotransmitter and its cognate receptor.

neuroscience↗

bioRxiv2017

A chemosensory switch couples genetic sex to behavioral valence

As a fundamental dimension of internal state, biological sex modulates neural circuits to generate naturally occurring 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, while masculinization of ADF is sufficient to make ascarosides attractive to hermaphrodites. Genetic sex modulates ADF function by tuning chemosensation: ADF is able to detect the ascaroside ascr#3 only in males, a consequence of cell-autonomous action of the master sexual regulator tra-1. Genetic sex regulates behavior in part through the conserved DMRT gene mab-3, whose male-specific expression in ADF promotes ascaroside attraction. 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. These results demonstrate that DMRT genes can functionally modulate shared neural circuits; moreover, they reveal an adaptive mechanism in which chromosomal sex controls a cell-autonomous switch that tunes sensory function, determines behavioral valence, and promotes reproductive fitness.

neuroscience↗

bioRxiv2017

Predator-secreted sulfolipids induce fear-like defense responses in C. elegans

Animals respond to predators by altering their behavior and physiological states, but the underlying signaling mechanisms are poorly understood. Using the interactions between Caenorhabditis elegans and its predator, Pristionchus pacificus, we show that neuronal perception by C. elegans of a predator-specific molecular signature induces instantaneous escape behavior and a prolonged reduction in oviposition. Chemical analysis revealed this predator-specific signature to consist of a class of sulfolipids, produced by a biochemical pathway required for developing predacious behavior and specifically induced by starvation. These sulfolipids are detected by four pairs of C. elegans amphid sensory neurons that act redundantly and recruit cyclic nucleotide-gated (CNG) or transient receptor potential (TRP) channels to drive both escape and reduced oviposition. Specific abolishment of predator-evoked C. elegans responses by the anti-anxiety drug sertraline as well as functional homology of the delineated signaling pathways suggests a conserved or convergent strategy for managing predator threats.

neuroscience↗