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Animals, including humans, can adapt to environmental stress through phenotypic plasticity. The free-living nematode Caenorhabditis elegans can adapt to harsh environments by undergoing a whole-animal change, involving exiting reproductive development and entering the stress-resistant dauer larval stage. The dauer is a dispersal stage with dauer-specific behaviors for finding and stowing onto carrier animals, but how dauers acquire these behaviors, despite having a physically limited nervous system of 302 neurons, is poorly understood.We compared dauer and reproductive development using whole-animal RNA sequencing at fine time points and at sufficient depth to measure transcriptional changes within single cells. We detected 8,042 genes differentially expressed during dauer and reproductive development and observed striking up-regulation of neuropeptide genes during dauer entry. We knocked down neuropeptide processing using sbt-1 mutants and demonstrate that neuropeptide signaling promotes the decision to enter dauer rather than reproductive development. We also demonstrate that during dauer neuropeptides modulate the dauer-specific nictation behavior (carrier animal-hitchhiking) and are necessary for switching from repulsion to CO₂ (a carrier animal cue) in nondauers to CO₂ attraction in dauers. We tested individual neuropeptides using CRISPR knockouts and existing strains and demonstrate that the combined effects of flp-10 and flp-17 mimic the effects of sbt-1 on nictation and CO₂ attraction. Through meta-analysis, we discovered similar up-regulation of neuropeptides in the dauer-like infective juveniles of diverse parasitic nematodes, suggesting the antiparasitic target potential of SBT-1. Our findings reveal that, under stress, increased neuropeptide signaling in C. elegans enhances their decision-making accuracy and expands their behavioral repertoire.

Dominant mutations in p97/VCP (valosin-containing protein) cause a rare multisystem degenerative disease with varied phenotypes that include inclusion body myopathy, Paget’s disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. p97 disease mutants have altered N-domain conformations, elevated ATPase activity, and altered cofactor association. We have now discovered a previously unidentified disease-relevant functional property of p97 by identifying how the cofactors p37 and p47 regulate p97 ATPase activity. We define p37 as, to our knowledge, the first known p97-activating cofactor, which enhances the catalytic efficiency ( k cₐₜ/ K ₘ) of p97 by 11-fold. Whereas both p37 and p47 decrease the K ₘ of ATP in p97, p37 increases the k cₐₜ of p97. In contrast, regulation by p47 is biphasic, with decreased k cₐₜ at low levels but increased k cₐₜ at higher levels. By deleting a region of p47 that lacks homology to p37 (amino acids 69–92), we changed p47 from an inhibitory cofactor to an activating cofactor, similar to p37. Our data suggest that cofactors regulate p97 ATPase activity by binding to the N domain. Induced conformation changes affect ADP/ATP binding at the D1 domain, which in turn controls ATPase cycling. Most importantly, we found that the D2 domain of disease mutants failed to be activated by p37 or p47. Our results show that cofactors play a critical role in controlling p97 ATPase activity, and suggest that lack of cofactor-regulated communication may contribute to p97-associated disease pathogenesis. Significance Age-associated degenerative diseases have similar pathogenic mechanisms related to defects in protein homeostasis. p97/VCP (valosin-containing protein) is essential for coordinating protein degradation and is mutated in a multisystem degenerative disease that affects the central nervous system, muscle, and bone. p97/VCP is an enzyme in the AAA ATPases (ATPases associated with diverse cellular activities) family, which takes apart ATP and uses this energy to perform pivotal functions. We found that p97/VCP cofactors control its enzymatic activity. p97/VCP disease mutants behave abnormally due to lack of appropriate control by these cofactors. Correcting the function of the disease-associated proteins may be a desirable approach to developing safe treatment for fatal degenerative diseases. The next steps are to screen and characterize large panels of compounds to identify potential drugs that may correct the malfunction.

Life in extreme environments is typically studied as a physiological problem, although the existence of extremophilic animals suggests that developmental and behavioral traits might also be adaptive in such environments. Here, we describe a new species of nematode, Tokorhabditis tufae , n. gen., n. sp., which was discovered from the alkaline, hypersaline, and arsenic-rich locale of Mono Lake, California. The new species, which offers a tractable model for studying animal-specific adaptations to extremophilic life, shows a combination of unusual reproductive and developmental traits. Like the recently described sister group Auanema , the species has a trioecious mating system comprising males, females, and self-fertilizing hermaphrodites. Our description of the new genus thus reveals that the origin of this uncommon reproductive mode is even more ancient than previously assumed, and it presents a new comparator for the study of mating-system transitions. However, unlike Auanema and almost all other known rhabditid nematodes, the new species is obligately live-bearing, with embryos that grow in utero, suggesting maternal provisioning during development. Finally, our isolation of two additional, molecularly distinct strains of the new genus—specifically from non-extreme locales—establishes a comparative system for the study of extremophilic traits in this model.

Organisms including bacteria, insects, and mammals make decisions to alter aspects of their development based on signals from the environment. The roundworm Caenorhabditis eleganscan escape environmental collapse by halting reproductive growth and entering the stress-resistant dauer larval stage. Dauer larvae are spore-like and have specialized behaviors for finding and stowing onto carrier animals for dispersal. The decision to enter dauer is an anticipatory decision that is based on the inputs of food, pheromone, and temperature.Here, I show that touch is an overlooked input into the dauer entry decision. Using quantitative dauer entry assays on CRISPR knock-ins and existing mutants in mechanosensation, I demonstrate that gentle, harsh, and piezo touch promote dauer entry. By measuring pheromone sensation and signal tranmission in mechnanosensation-defective mutants, I show that mechanosensation likely inputs into the decision in parallel with pheromone. Further confirmation that touch promotes dauer entry is provided using direct mechanical stimulation of C. elegans, and I provide a plausible role for touch in sensing dauer-promoting weather and crowding conditions.Using RNA-seq, I also show that 8,042 genes are differentially expressed between dauer and reproductive development. Within this dataset, we observed the striking up-regulation of 64 neuropeptide genes (encoding 215 peptides) during dauer. By comparison, the entire human genome contains 97 neuropeptide genes (encoding 270 peptides). In particular, we observed coordinated up-regulation of the FMRFamide-like neuropeptides (FLPs). Using sbt-1 mutants to knock down neuropeptide processing, we demonstrate that peptidergic signaling promotes the dauer entry decision, promotes vigorous waving during the dauer-specific nictation behavior (carrier animal-hitchhiking), and is necessary for switching from repulsion to CO2 (a carrier animal cue) in non-dauers to CO2 attraction in dauers. By testing individual neuropeptides using CRISPR knockouts and existing strains, we show that 7 FLPs promote dauer entry while 4 FLPs inhibit. I therefore propose plausible roles for these FLPs in acting downstream of and/or modulating the sensation of food, pheromone, temperature, and touch inputs. We also demonstrate that FLP10/FLP-17, which are expressed in the CO2-sensing BAG neuron, promote CO2 chemotaxis and nictation in dauers. These findings reveal that neuropeptides can alter decision-making and behavior during C. elegansdauer entry. Through a meta-analysis, we discovered similar up-regulation of FLPs in the dauer-like infective juveniles of diverse parasitic nematodes, suggesting that this may be an ancient mechanism for expanding the behavioral repertoire of nematodes.Further utilizing our RNA-seq dataset, I identified several markers for conveniently tracking and manipulating the dauer entry decision. These include col-183 (which tracks dauer fate in the hypodermis), ets-10 (neurons and intestine), nhr-246 (intestine and muscle), and led-1 (reproductive fate in hypodermis). Using condition shift experiments, we demonstrate that the dauer markers label animals during dauer-commitment. We show that these markers can be used to manipulate the entry decision by driving the reproduction-promoting gene daf-9/Cytochrome P450 under the control of the dauer-commitment markers. We further demonstrate that the markers can be used to track tissue coordination and its breakdown in partial dauer mutants, and propose strategies for using the markers to identify the intercellular signals that coordinate the dauer entry decision.