Xu T et al. (2023) PLoS Genet "A ZTF-7/RPS-2 complex mediates the cold-warm response in C. elegans."

Feng X, Liao S, Huang M, Fu C, Guang S, Chen X, Jin Q, Xu T, Xu D, Zhu C, Huang X

[PLoS Genet, 2023]

Temperature greatly affects numerous biological processes in all organisms. How multicellular organisms respond to and are impacted by hypothermic stress remains elusive. Here, we found that cold-warm stimuli induced depletion of the RNA exosome complex in the nucleoli but enriched it in the nucleoplasm. To further understand the function and mechanism of cold-warm stimuli, we conducted forward genetic screening and identified ZTF-7, which is required for RNA exosome depletion from nucleoli upon transient cold-warm exposure in C. elegans. ZTF-7 is a putative ortholog of human ZNF277 that may contribute to language impairments. Immunoprecipitation followed by mass spectrometry (IP-MS) found that ZTF-7 interacted with RPS-2, which is a ribosomal protein of the small subunit and participates in pre-rRNA processing. A partial depletion of RPS-2 and other proteins of the small ribosomal subunit blocked the cold-warm stimuli-induced reduction of exosome subunits from the nucleoli. These results established a novel mechanism by which C. elegans responds to environmental cold-warm exposure.

Xu, T. et al. (2011) International Worm Meeting "The Role of Nicotinic Acetylcholine Receptors in Antipsychotic-induced Phenotypes in Caenorhabditis elegans."

Wang, X., Xu, T., Cohen, BM, Hao, L., Buttner, EN

[International Worm Meeting, 2011]

The atypical antipsychotic clozapine has greater therapeutic efficacy than other medications in the treatment of schizophrenia, but the molecular mechanisms underlying clozapine's effects are poorly understood. The a7-nicotinic acetylcholine receptor (nAchR) has been implicated in the genetics of schizophrenia. Moreover, the heavy smoking behavior of schizophrenics may be a form of self-medication. Clozapine induces early larval arrest in C. elegans. A genome-wide RNA interference (RNAi) screen for suppressors of clozapine-induced larval arrest yielded acr-7, a homolog of the a7-nAchR. We obtained an acr-7 knockout strain and backcrossed this strain to wild type six times. We then confirmed our RNAi knockdown result by demonstrating that the acr-7 knockout suppresses clozapine-induced larval arrest. Interestingly, our preliminary observations suggest that knockout of acr-7 also suppresses clozapine-induced inhibition of locomotion in C. elegans. This finding indicates that acr-7(lf) has pleiotropic effects and that acr-7 may mediate both developmental and behavioral phenotypes of antipsychotic drugs in C. elegans. Therefore, detailed characterization of the genetic, cell biological, and behavioral roles of acr-7 may provide insight into the effects of antipsychotic drugs on neuronal functions. Future experiments will include: 1) expression studies of acr-7 in C. elegans using GFP fusion constructs; 2) additional developmental and behavioral experiments to test whether acr-7 mediates the effects of antipsychotic drugs other than clozapine; 3) electrophysiological studies of acr-7 in heterologous systems; 4) epistasis studies of acr-7 and genes within the insulin sigaling pathway which also mediates clozapine's effects in C. elegans and mammals.

Xu T et al. (2017) Chemosphere "Behavioral deficits and neural damage of Caenorhabditis elegans induced by three rare earth elements."

Bao J, Lei L, Wu S, Xu T, Hu J, Li Z, Zhang M, He D, Wu T

[Chemosphere, 2017]

Rare earth elements (REEs) are widely used in industry, agriculture, medicine and daily life in recent years. However, environmental and health risks of REEs are still poorly understood. In this study, neurotoxicity of trichloride neodymium, praseodymium and scandium were evaluated using nematode Caenorhabditis elegans as the assay system. Median lethal concentrations (48h) were 99.9, 157.2 and 106.4mg/L for NdCl3, PrCl3 and ScCl3, respectively. Sublethal dose (10-30mg/L) of these trichloride salts significantly inhibited body length of nematodes. Three REEs resulted in significant declines in locomotor frequency of body bending, head thrashing and pharyngeal pumping. In addition, mean speed and wavelength of crawling movement were significantly reduced after chronic exposure. Using transgenic nematodes, we found NdCl3, PrCl3 and ScCl3 resulted in loss of dendrite and soma of neurons, and induced down-expression of dat-1::GFP and unc-47::GFP. It indicates that REEs can lead to damage of dopaminergic and GABAergic neurons. Our data suggest that exposure to REEs may cause neurotoxicity of inducing behavioral deficits and neural damage. These findings provide useful information for understanding health risk of REE materials.

Xu, T. et al. (2019) International Worm Meeting "How does an animal move? An integrative model of C. elegans forward locomotion."

Kawano, T., Xu, T., Po, M., Shao, S., Wu, M., Zhen, M., Huo, J., Wen, Q., Lu, Y.

[International Worm Meeting, 2019]

Descending signals from the brain play critical roles in controlling and modulating locomotion kinematics. In the Caenorhabditis elegans nervous system, descending AVB premotor interneurons exclusively form gap junctions with the B-type motor neurons that execute forward locomotion. We combined genetic analysis, optogenetic manipulation, calcium imaging, and computational modeling to elucidate the function of AVB-B gap junctions during forward locomotion. First, we found that some B-type motor neurons generate rhythmic activity, constituting distributed oscillators. Second, AVB premotor interneurons use their electric inputs to drive bifurcation of B-type motor neuron dynamics, triggering their transition from stationary to oscillatory activity. Third, proprioceptive couplings between neighboring B-type motor neurons entrain the frequency of body oscillators, forcing coherent bending wave propagation. Despite substantial anatomical differences between the motor circuits of C. elegans and higher model organisms, converging principles govern coordinated locomotion.

Xu T et al. (2022) Food Funct "Longevity-promoting properties of ginger extract in Caenorhabditis elegans via the insulin/IGF-1 signaling pathway."

Tao M, Pan S, Xu T, Wu T, Li R, Xu X

[Food Funct, 2022]

Ginger is a traditional medicinal and edible plant with multiple health-promoting properties. Nevertheless, the effects and potential mechanism of ginger on antiaging remain unknown. The aim of this study was to comprehend the antiaging effects and potential mechanism of ginger in Caenorhabditis elegans (C. elegans). The current findings showed that the lifespan of C. elegans was prolonged by 23.16% with the supplementation of 60 μg mL-1 ginger extract (GE), and the extension of lifespan was mainly attributed to the major bioactive compounds in GE, 6-, 8-, 10-gingerol and 6-, 8-, 10-shogaol. Subsequently, GE promoted healthy aging by improving nematode movement and attenuating lipofuscin accumulation, and enhanced stress tolerance by up-regulating the expression of stress-related genes and activating DAF-16 and SKN-1. Moreover, lifespan assays of relative mutants revealed that GE mediated extension of lifespan via the insulin/IGF-1 signaling (IIS) pathway. In summary, GE endowed nematodes (C. elegans) with longevity and stress resistance in an IIS pathway dependent manner.

Xu T et al. (2017) EMBO J "RBPJ/CBF1 interacts with L3MBTL3/MBT1 to promote repression of Notch signaling via histone demethylase KDM1A/LSD1."

Kovall RA, Conlon KP, Rual JF, Govindarajoo B, Hall D, Dou Y, Ho DM, Bartkuhn M, Nesvizhskii AI, Milon E, Sun Y, Xu T, Ertl I, Zhang H, Borggrefe T, Zhang Y, Elenitoba-Johnson KS, Park SS, Hori K, Anhezini L, Kuick R, Ha K, Basrur V, Lee CY, Ceron J, Giaimo BD, Ferrante F

[EMBO J, 2017]

Notch signaling is an evolutionarily conserved signal transduction pathway that is essential for metazoan development. Upon ligand binding, the Notch intracellular domain (NOTCH ICD) translocates into the nucleus and forms a complex with the transcription factor RBPJ (also known as CBF1 or CSL) to activate expression of Notch target genes. In the absence of a Notch signal, RBPJ acts as a transcriptional repressor. Using a proteomic approach, we identified L3MBTL3 (also known as MBT1) as a novel RBPJ interactor. L3MBTL3 competes with NOTCH ICD for binding to RBPJ In the absence of NOTCH ICD, RBPJ recruits L3MBTL3 and the histone demethylase KDM1A (also known as LSD1) to the enhancers of Notch target genes, leading to H3K4me2 demethylation and to transcriptional repression. Importantly, invivo analyses of the homologs of RBPJ and L3MBTL3 in Drosophila melanogaster and Caenorhabditis elegans demonstrate that the functional link between RBPJ and L3MBTL3 is evolutionarily conserved, thus identifying L3MBTL3 as a universal modulator of Notch signaling in metazoans.

Xu T et al. (2016) Bull Environ Contam Toxicol "Chronic Exposure to Perfluorooctane Sulfonate Reduces Lifespan of Caenorhabditis elegans Through Insulin/IGF-1 Signaling."

He D, Wu J, Li D, Wu S, Xu T, Li P, Raley-Susman KM

[Bull Environ Contam Toxicol, 2016]

Perfluorooctane sulfonate (PFOS) is a persistent organic pollutant. Although multiple adverse effects of PFOS have been demonstrated, whether PFOS can accelerate aging and affect animal longevity remains unknown. In Caenorhabditis elegans, we found that a 50h exposure to 0.2-200M PFOS reduced lifespan in a concentration dependent manner. In transgenic nematodes, lifespans are affected by mutations of daf-16, daf-2 or age-1 genes, which are related to the Insulin/IGF-1 Signaling pathway (IIS). PFOS exposure caused an additional reduction in average lifespan in daf-2(e1370) and daf-16b(KO) nematodes. In contrast, daf-16(mu86) nematodes showed no additional reduction with PFOS exposure and age-1(hx546) mutants did not exhibit a reduction in lifespan with PFOS exposure, compared with wildtype nematodes. Overall, our findings demonstrate that PFOS exposure accelerates aging and shortens longevity of animals. The PFOS-induced effect may involve genes of the IIS pathway, particularly daf-16 and age-1.

Xu T et al. (2017) Toxicol Res (Camb) "Tris(2-chloroethyl) phosphate (TCEP) and tris(2-chloropropyl) phosphate (TCPP) induce locomotor deficits and dopaminergic degeneration in Caenorhabditis elegans."

Wu S, Xu T, Lei L, Li P, He D

[Toxicol Res (Camb), 2017]

Organophosphate flame retardants (PFRs) are a new class of flame retardants. The health risks of PFRs have received attention recently. However, little is known about the potential toxicity of PFRs on the nervous system. Herein, we evaluated the neurotoxic effects of two typical PFRs, tris(2-chloroethyl) phosphate (TCEP) and tris(2-chloropropyl) phosphate (TCPP), using <i>Caenorhabditis elegans</i>. Median lethal concentrations of chronic exposure (3 d) were 1578 and 857 mg L^-1 for TCEP and TCPP, respectively. The sublethal dose of TCEP or TCPP significantly inhibited the body length and reduced the lifespans of nematodes. 500 mg L^-1 and above of TCEP/TCPP led to a significant decline in the locomotor frequency of body bending and head thrashing. Furthermore, their exposure reduced the crawling speed and the frequency of bending oscillation of nematodes. This indicates that TCEP/TCPP induces locomotor deficits, along with Parkinsonian-like movement impairment including bradykinesia and hypokinesia. Using transgenic worms, we found that TCEP/TCPP could induce down-expression of P _<i>dat</i>-1 and resulted in the degeneration of dopaminergic neurons, especially PDE neurons. Moreover, TCEP/TCPP induced over-expression of <i>unc-54</i>, which indicates the aggregation of -synuclein in the process of degeneration. These findings suggest the neurotoxicity risks of organophosphorus flame retardants, which are associated with the locomotor deficits and dopaminergic degeneration.

Xu T et al. (2018) Proc Natl Acad Sci U S A "Descending pathway facilitates undulatory wave propagation in Caenorhabditis elegans through gap junctions."

Wen Q, Lu Y, Po M, Zhen M, Shao S, Xu T, Wu M, Kawano T, Huo J

[Proc Natl Acad Sci U S A, 2018]

Descending signals from the brain play critical roles in controlling and modulating locomotion kinematics. In the <i>Caenorhabditis elegans</i> nervous system, descending AVB premotor interneurons exclusively form gap junctions with the B-type motor neurons that execute forward locomotion. We combined genetic analysis, optogenetic manipulation, calcium imaging, and computational modeling to elucidate the function of AVB-B gap junctions during forward locomotion. First, we found that some B-type motor neurons generate rhythmic activity, constituting distributed oscillators. Second, AVB premotor interneurons use their electric inputs to drive bifurcation of B-type motor neuron dynamics, triggering their transition from stationary to oscillatory activity. Third, proprioceptive couplings between neighboring B-type motor neurons entrain the frequency of body oscillators, forcing coherent bending wave propagation. Despite substantial anatomical differences between the motor circuits of <i>C. elegans</i> and higher model organisms, converging principles govern coordinated locomotion.

Fire A et al. (1994) Worm Breeder's Gazette "Vectorology I: New lacZ Vectors (Building a Better Gene Trap)."

Fire A, Xu SQ

[Worm Breeder's Gazette, 1994]

Vectorology I: New lacZ vectors ("building a better gene trap") Andrew Fire and SiQun Xu Carnegie Institution of Washington, Baltimore, Md 21210