Chen HW et al. (2002) Mol Cell Biol "CKA, a novel multidomain protein, regulates the JUN N-terminal kinase signal transduction pathway in Drosophila."

Oh SW, Gutkind JS, Chen HW, Chen X, Hou SX, Marinissen MJ, Perrimon N, Melnick M

[Mol Cell Biol, 2002]

The Drosophila melanogaster JUN N-terminal kinase (DJNK) and DPP (decapentaplegic) signal transduction pathways coordinately regulate epithelial cell sheet movement during the process of dorsal closure in the embryo. By a genetic screen of mutations affecting dorsal closure in Drosophila, we have now identified a multidomain protein, connector of kinase to AP-1 (cka), that functions in the DJNK pathway and controls the localized expression of dpp in the leading-edge cells. We have also investigated how CKA acts. This unique molecule forms a complex with HEP (DJNKK), BSK (DJNK), DJUN, and DFOS. Complex formation activates BSK kinase, which in turn phosphorylates and activates DJUN and DFOS. These data suggest that CKA represents a novel molecule regulating AP-1 activity by organizing a molecular complex of kinases and transcription factors, thus coordinating the spatial-temporal expression of AP-1-regulated genes.

Kurshakova M et al. (2007) Mol Cell "Evolutionarily conserved E(y)2/Sus1 protein is essential for the barrier activity of Su(Hw)-dependent insulators in Drosophila."

Georgiev P, Golovnin A, Kurshakova M, Georgieva S, Maksimenko O, Pulina M, Krasnov A

[Mol Cell, 2007]

Chromatin insulators affect interactions between promoters and enhancers/silencers and function as barriers for spreading of repressive chromatin. The Su(Hw) protein is responsible for activity of the best-studied Drosophila insulators. Here we demonstrate that an evolutionarily conserved protein, E(y)2/Sus1, is recruited to the Su(Hw) insulators via binding to the zinc-finger domain of Su(Hw). Partial inactivation of E(y)2 in a weak mutation, e(y)2(u1), impairs only the barrier, but not the enhancer-blocking, activity of the Su(Hw) insulators. Whereas neither su(Hw)(-) nor e(y)2(u1) affects fly viability, their combination proves lethal, testifying to functional interaction between Su(Hw) and E(y)2 in vivo. Apparently, different domains of Su(Hw) recruit proteins responsible for enhancer-blocking and for the barrier activity.

Balla KM et al. (2019) PLoS One "Natural variation in the roles of C. elegans autophagy components during microsporidia infection."

Balla KM, Troemel ER, Lazetic V

[PLoS One, 2019]

Natural genetic variation can determine the outcome of an infection, and often reflects the co-evolutionary battle between hosts and pathogens. We previously found that a natural variant of the nematode Caenorhabditis elegans from Hawaii (HW) has increased resistance against natural microsporidian pathogens in the Nematocida genus, when compared to the standard laboratory strain of N2. In particular, HW animals can clear infection, while N2 animals cannot. In addition, HW animals have lower levels of initial colonization of Nematocida inside intestinal cells, compared to N2. Here we investigate how this natural variation in resistance relates to autophagy. We found that there is much better targeting of autophagy-related machinery to parasites under conditions where they are cleared. In particular, ubiquitin targeting to Nematocida cells correlates very well with their subsequent clearance in terms of timing, host strain and age, as well as species of Nematocida. Furthermore, clearance correlates with targeting of the LGG-2/LC3 autophagy protein to parasite cells, with HW animals having much more efficient targeting of LGG-2 to parasite cells than N2 animals. Surprisingly, however, we found that LGG-2 is not required to clear infection. Instead, we found that LGG-2/LC3 regulates Nematocida colonization inside intestinal cells. Interestingly, LGG-2/LC3 regulates intracellular colonization only in the HW strain, and not in N2. Altogether these results demonstrate that there is natural genetic variation in an LGG-2-dependent process that regulates microsporidia colonization inside intestinal cells, although not microsporidia clearance.

Po MD et al. (2012) Neuron "Releasing the inner inhibition for axon regeneration."

Po MD, Calarco JA, Zhen M

[Neuron, 2012]

The adult mammalian central nervous system exhibits restricted regenerative potential. Chen etal. (2011) and El Bejjani and Hammarlund (2012) used Caenorhabditis elegans to uncover intrinsic factors that inhibit regeneration of axotomized mature neurons, opening avenues for potential therapeutics.

Zhu Z et al. (2015) Sci Rep "Compatibility between mitochondrial and nuclear genomes correlates with the quantitative trait of lifespan in Caenorhabditis elegans."

Wang J, Huang S, Zhu Z, Zeng F, Lu Q

[Sci Rep, 2015]

Mutations in mitochondrial genome have epistatic effects on organisms depending on the nuclear background, but a role for the compatibility of mitochondrial-nuclear genomes (mit-n) in the quantitative nature of a complex trait remains unexplored. We studied a panel of recombinant inbred advanced intercrossed lines (RIAILs) of C. elegans that were established from a cross between the N2 and HW strains. We determined the HW nuclear genome content and the mitochondrial type (HW or N2) of each RIAIL strain. We found that the degree of mit-n compatibility was correlated with the lifespans but not the foraging behaviors of RIAILs. Several known aging-associated QTLs individually showed no relationship with mitotypes but collectively a weak trend consistent with a role in mit-n compatibility. By association mapping, we identified 293 SNPs that showed linkage with lifespan and a relationship with mitotypes consistent with a role in mit-n compatibility. We further found an association between mit-n compatibility and several functional characteristics of mitochondria as well as the expressions of genes involved in the respiratory oxidation pathway. The results provide the first evidence implicating mit-n compatibility in the quantitative nature of a complex trait, and may be informative to certain evolutionary puzzles on hybrids.

Silverstein NJ et al. (2017) Immunity "Interleukin-17: Why the Worms Squirm."

Huh JR, Silverstein NJ

[Immunity, 2017]

IL-17 is a cytokine known primarily for its role in inflammation. In a recent issue of Nature, Chen etal. (2017) demonstrate that IL-17 plays a neuromodulatory role in Caenorhabditis elegans by acting directly on neurons to amplify neuronal responses to stimuli and produce changes in animal behavior.

Carrillo, M.A. et al. (2013) International Worm Meeting "Oxygen sensing neurons control carbon dioxide response in C. elegans."

Carrillo, M.A., Okubo, R., Guillermin, M.L., Rengarajan, S., Hallem, E.A.

[International Worm Meeting, 2013]

Many sensory behaviors are flexible, allowing animals to generate context-appropriate responses to changing environmental conditions. To investigate the neural basis of behavioral flexibility, we are examining the regulation of carbon dioxide (CO2) response in C. elegans. CO2 is a critical sensory cue for many animals, mediating responses to food, conspecifics, predators, and hosts. In C. elegans, CO2 response is regulated by the polymorphic neuropeptide receptor NPR-1: animals with the N2 variant of npr-1 avoid CO2, while animals with the Hawaiian (HW) variant or an npr-1 loss-of-function (lf) mutation appear virtually insensitive to CO2. We examined the mechanism by which NPR-1 regulates CO2 avoidance behavior. We found that ablation of URX neurons in npr-1(lf) mutants restores CO2 avoidance, suggesting that NPR-1 enables CO2 avoidance by inhibiting URX. In npr-1(lf) mutants, O2-induced activation of URX inhibits CO2 avoidance. Mutation of the URX-expressed neuropeptide genes flp-19 and flp-8 also restores CO2 avoidance to npr-1(lf) mutants, consistent with the possibility that neuropeptide release by URX regulates CO2 response. In addition, we found that both HW and npr-1(lf) animals avoid CO2 under low O2 conditions, when URX neurons are inactive. Our results suggest that in HW and npr-1(lf) animals, URX neurons control CO2 response by coordinating the response to CO2 with the response to ambient O2 such that CO2 is repulsive at low ambient O2 but neutral at high ambient O2. The fact that wild C. elegans strains contain the HW allele of npr-1 suggests that O2-dependent regulation of CO2 avoidance is likely to be an ecologically relevant mechanism by which nematodes navigate gas gradients.

Pradhan, Sreeparna et al. (2019) International Worm Meeting "Environmental programming of adult foraging behavior."

Hendricks, Michael, Quilez, Sabrina Rita, Homer, Kai, Pradhan, Sreeparna

[International Worm Meeting, 2019]

Animals tune their foraging strategies by using past experience to estimate current resource availability and distribution. Previous studies have reported plasticity in foraging strategies in C. elegans over short time scales over a few hours in response to environmental fluctuations. Genetic variation between different wild isolates are also known to affect foraging decisions, with the lab wild-type N2 strain being the least exploratory and the wild HW CB4856 strain being the most exploratory. We explored whether foraging behavior can be tuned over the time scale of the lifetime of an individual. Stressful environmental conditions like scarcity of food in early larval stages directly affect C. elegans development inducing entry into the dauer developmental arrest phase. We examined adult foraging strategies in post-dauer animals of different genetic backgrounds. Our results show that HW post-dauers have permanently reduced adult foraging behavior, but this long-term plasticity is absent in the lab adapted N2 strain. We also observed changes in the temporal pattern of food search in HW post-dauers, coupled with a high propensity of reversals and turns. We then investigated the neural correlates of this permanent change in behavior, and simultaneously imaged calcium transients in AVA, AIB and RIM which form a local interneuron circuit controlling reversal output. Our results indicate that post-dauer HWs have higher dynamic activity in this circuit in both presence and absence of food cues. We next examined known polymorphisms between the N2 and HW strains to determine the genetic basis of between-strain differences in long-term plasticity. Our work shows that adult foraging behaviour is tuned by developmental experience and involves altering the dynamics of a core navigation circuit, and this plasticity is dependent on the genetic background and life history of the strain.

Glater EE et al. (2014) G3 (Bethesda) "Multigenic natural variation underlies Caenorhabditis elegans olfactory preference for the bacterial pathogen Serratia marcescens."

Glater EE, Bargmann CI, Rockman MV

[G3 (Bethesda), 2014]

The nematode Caenorhabditis elegans can use olfaction to discriminate among different kinds of bacteria, its major food source. We asked how natural genetic variation contributes to choice behavior, focusing on differences in olfactory preference behavior between two wild-type C. elegans strains. The laboratory strain N2 strongly prefers the odor of Serratia marcescens, a soil bacterium that is pathogenic to C. elegans, to the odor of Escherichia coli, a commonly used laboratory food source. The divergent Hawaiian strain CB4856 has a weaker attraction to Serratia than the N2 strain, and this behavioral difference has a complex genetic basis. At least three quantitative trait loci (QTLs) from the CB4856 Hawaii strain (HW) with large effect sizes lead to reduced Serratia preference when introgressed into an N2 genetic background. These loci interact and have epistatic interactions with at least two antagonistic QTLs from HW that increase Serratia preference. The complex genetic architecture of this C. elegans trait is reminiscent of the architecture of mammalian metabolic and behavioral traits.

Artan M et al. (2016) Dev Cell "Heat FLiPs a Hormonal Switch for Longevity."

Lee SV, An SW, Artan M

[Dev Cell, 2016]

Temperature-sensing neurons in C.elegans reduce the life-shortening effects of high temperatures via steroid signaling. In this issue of Developmental Cell, Chen etal. (2016) elucidate the underlying mechanisms by which the transcription factor CREB induces the neuropeptide FLP-6 in the temperature-sensing neurons to counteract the life-shortening effects of high temperature.