Deng H et al. (2007) Genetics "The Flightless I homolog, fli-1, regulates anterior/posterior polarity, asymmetric cell division and ovulation during Caenorhabditis elegans development."

Deng H, Xia D, Zhang H

[Genetics, 2007]

Flightless I (Fli I) is an evolutionarily conserved member of the gelsolin family, containing actin binding and severing activity in vitro. The physiological function of Fli I during animal development remains largely undefined. In this study, we reveal a key role of the C. elegans Fli I homolog, fli-1, in specifying asymmetric cell division and establishing anterior-posterior polarity in the zygote. The fli-1 gene also regulates the cytokinesis of somatic cells, the development of germline, and interacts with the phosphoinositol signaling pathway in the regulation of ovulation. The fli-1 reporter gene shows that the localization of FLI-1 coincides with actin-rich regions, and the actin cytoskeleton is impaired in many tissues in the fli-1 mutants. Furthermore, the function of fli-1 in C. elegans can be functionally substituted by the Drosophila Fli I. Our studies demonstrate that fli-1 plays an important role in regulating the actin-dependent events during C. elegans development.

Deng H et al. (2007) Dev Biol "Transcription factor NFY globally represses the expression of the C. elegans Hox gene Abdominal-B homolog egl-5."

Sun Y, Yan L, Deng H, Tian E, Luo X, Chen Y, Han J, Zhang Y, Hou W, Zhang H

[Dev Biol, 2007]

The C. elegans Hox gene egl-5 (ortholog of Drosophila Abdominal-B) is expressed in multiple tissues in the tail region and is involved in tail patterning. In this study, we identify and clone the corresponding C. elegans orthologs of the components of the heterotrimeric transcription factor NFY, nfya-1, nfyb-1 and nfyc-1 and demonstrate that mutations in these components result in the ectopic expression of egl-5 outside of its normal expression domains. The NFYA-1 protein forms a complex with NFYB-1 and NFYC-1, specifically recognizing the CCAAT box. Mutating a CCAAT box in the proximal promoter of egl-5 also leads to the derepression of egl-5, suggesting a direct role for the NFY complex in the regulation of egl-5. In addition, we show that the NFY complex interacts with the MES-2/MES-6 PcG complex in Hox gene regulation. Thus, our studies unravel a physiological function of NFY in establishing the spatially restricted expression pattern of egl-5.

Deng H et al. (2021) Proc Natl Acad Sci U S A "SLC-30A9 is required for Zn2+ homeostasis, Zn2+ mobilization, and mitochondrial health."

Deng H, Feng Y, Li H, Guo M, Chen C, Zhao Y, Xie T, Fu W, Miao L, Chen L, Qiao X, Shen K, Wang X

[Proc Natl Acad Sci U S A, 2021]

The trace element zinc is essential for many aspects of physiology. The mitochondrion is a major Zn2+ store, and excessive mitochondrial Zn2+ is linked to neurodegeneration. How mitochondria maintain their Zn2+ homeostasis is unknown. Here, we find that the SLC-30A9 transporter localizes on mitochondria and is required for export of Zn2+ from mitochondria in both Caenorhabditis elegans and human cells. Loss of slc-30a9 leads to elevated Zn2+ levels in mitochondria, a severely swollen mitochondrial matrix in many tissues, compromised mitochondrial metabolic function, reductive stress, and induction of the mitochondrial stress response. SLC-30A9 is also essential for organismal fertility and sperm activation in C. elegans, during which Zn2+ exits from mitochondria and acts as an activation signal. In slc-30a9-deficient neurons, misshapen mitochondria show reduced distribution in axons and dendrites, providing a potential mechanism for the Birk-Landau-Perez cerebrorenal syndrome where an SLC30A9 mutation was found.

Yu Z et al. (2015) Ecotoxicol Environ Saf "The combinational effects between sulfonamides and metals on nematode Caenorhabditis elegans."

Deng H, Yin D, Yu Z

[Ecotoxicol Environ Saf, 2015]

As emerging pollutants, antibiotic sulfonamides are continuously emitted into the environment and encounter those already-existing contaminants, e.g., heavy metals, which may cause toxicity interactions in polluted habitats. So far, the sulfonamide mixture effects and the combinational effects between sulfonamides and metals have been seldom studied. In this study, lifespan, lethality (24 and 120 h), locomotion behavior and growth (96 h) of Caenorhabditis elegans were measured after exposure to mixtures containing sulfonamides (sulfadiazine, sulfapyridine, sulfamethoxazole and sulfamethazine as representatives) and/or metals (cadmium, copper, lead and zinc as representatives) at environmental concentrations. Results showed that sulfonamides did not cause acute (24 h) lethality at chosen concentrations, but they decreased the lifespan in a concentration dependent fashion. Moreover, sulfonamide mixtures caused synergisms at higher concentrations but antagonisms at lower concentrations on the subacute (120 h) lethal effects. The toxicity interactions of sulfonamide mixtures were addition action on body bending frequency, and antagonism on reversal movement and body length. In sulfonamide and metal mixtures, the toxicity interactions were different in acute and subacute lethal results, indicating the influence of the exposure time. According to the comparison among effects of mixtures containing sulfonamides and/or metals, subacute lethality of sulfonamides was enhanced by metals based on the synergistic mixture effects, while their inhibitions on the growth and behavior were weakened by metals based on the antagonistic mixture effects. Our findings highlighted studies on combinational effects between emerging and common contaminants for more accurate environmental risk evaluation, and also urged further mechanism studies.

Sun J et al. (2013) Exp Parasitol "Parasitism of secondary-stage juvenile of Heterodera glycines and four larva stages of Caenorhabditis elegans by Hirsutella spp."

Sun J, Xie H, Xiang M, Liu X, Qiu J

[Exp Parasitol, 2013]

The fungi Hirsutella rhossiliensis and Hirsutella minnesotensis generally parasitize only plant-parasitic nematodes in nature but parasitize the bacterivorous nematode Caenorhabditis elegans on agar plates. To establish a model system for studying the interaction between fungi and nematodes, we compared the parasitism of the first- to fourth-stage larvae (L1-L4) of C. elegans and second-stage juvenile (J2) of Heterodera glycines by twenty isolates of Hirsutella spp. Although parasitism differed substantially among isolates, both H. minnesotensis and H. rhossiliensis parasitized a higher percentage of H. glycines J2s than of C. elegans larvae. Parasitism of C. elegans L1s was correlated with parasitism of H. glycines J2s. Parasitism of C. elegans by H. rhossiliensis and H. minnesotensis was negatively correlated with larva size and motility, i.e., parasitism was higher for the younger stages. The C. elegans L1 is recommended for studying parasitism of nematodes by H. rhossiliensis and H. minnesotensis.

Fei YJ et al. (2000) J Biol Chem "A novel H(+)-coupled oligopeptide transporter (OPT3) from Caenorhabditis elegans with a predominant function as a H(+) channel and an exclusive expression in neurons."

Leibach FH, Romero MF, Krause MW, Huang W, Ganapathy V, Fei YJ, Liu JC

[J Biol Chem, 2000]

We have cloned and functionally characterized a novel, neuron-specific, H(+)-coupled oligopeptide transporter (OPT3) from Caenorhabditis elegans that functions predominantly as a H(+) channel. The opt3 gene is approximately 4.4 kilobases long and consists of 13 exons. The cDNA codes for a protein of 701 amino acids with 11 putative transmembrane domains. When expressed in mammalian cells and in Xenopus laevis oocytes, OPT3 cDNA induces H(+)-coupled transport of the dipeptide glycylsarcosine. Electrophysiological studies of the transport function of OPT3 in Xenopus oocytes show that this transporter, although capable of mediating H(+)-coupled peptide transport, functions predominantly as a H(+) channel. The H(+) channel activity of OPT3 is approximately 3-4-fold greater than the H(+)/peptide cotransport activity as determined by measurements of H(+) gradient-induced inward currents in the absence and presence of the dipeptide using the two-microelectrode voltage clamp technique. A downhill influx of H(+) was accompanied by a large intracellular acidification as evidenced from the changes in intracellular pH using an ion-selective microelectrode. The H(+) channel activity exhibits a K(0.5)(H) of 1.0 microM at a membrane potential of -50 mV. At the level of primary structure, OPT3 has moderate homology with OPT1 and OPT2, two other H(+)-coupled oligopeptide transporters previously cloned from C. elegans. Expression studies using the opt3::gfp fusion constructs in transgenic C. elegans demonstrate that opt3 gene is exclusively expressed in neurons. OPT3 may play an important physiological role as a pH balancer in the maintenance of H(+) homeostasis in C. elegans.

Wilson PA et al. (1982) Parasitology "Strongyloides ratti (homogonic): the time-course of early migration in the generalized host deduced from experiments in lactating rats."

Steven GE, Simpson NE, Wilson PA

[Parasitology, 1982]

Unsuckled mother rats given a 1 h suckling stimulus 3 h after subcutaneous injection of an exact dose of homogonic Strongyloides ratti allow fewer worms to develop in their intestines by day 9 than nulliparous rats (Wilson & Simpson, 1981). This effect is studied in more detail in terms of the length of time between weaning and stimulus (W leads to S) and injection and stimulus (I leads to S). It was observable with a W leads to S of 30 h but this and a period of 5 h were less effective than 24 h. With W leads to S constant at 24 h, significantly more worms developed in mothers when I leads to S was 24 h compared to 3 h and 10 h (P less than 0.005). The data, combined with those from nulliparous controls, are presented as a measure of the change with time of numbers of larvae in that compartment of the system which gives access to the stimulated mammary gland. It is argued that the particular compartment is the local lymph node draining the injection site and that the kinetics deduced are applicable to migration in the rat in general.

Miller DL et al. (2007) Proc Natl Acad Sci U S A "Hydrogen sulfide increases thermotolerance and lifespan in Caenorhabditis elegans."

Miller DL, Roth MB

[Proc Natl Acad Sci U S A, 2007]

Hydrogen sulfide (H(2)S) is naturally produced in animal cells. Exogenous H(2)S has been shown to effect physiological changes that improve the capacity of mammals to survive in otherwise lethal conditions. However, the mechanisms required for such alterations are unknown. We investigated the physiological response of Caenorhabditis elegans to H(2)S to elucidate the molecular mechanisms of H(2)S action. Here we show that nematodes exposed to H(2)S are apparently healthy and do not exhibit phenotypes consistent with metabolic inhibition. Instead, animals exposed to H(2)S are thermotolerant and long-lived. These phenotypes require SIR-2.1 activity but are genetically independent of the insulin signaling pathway, mitochondrial dysfunction, and caloric restriction. These studies suggest that SIR-2.1 activity may translate environmental change into physiological alterations that improve survival. It is interesting to consider the possibility that the mechanisms by which H(2)S increases thermotolerance and lifespan in nematodes are conserved and that studies using C. elegans may help explain the beneficial effects observed in mammals exposed to H(2)S.

Yu Z et al. (2013) J Hazard Mater "Inhibitions on the behavior and growth of the nematode progeny after prenatal exposure to sulfonamides at micromolar concentrations."

Zhang J, Deng H, Yin D, Chen X, Yu Z

[J Hazard Mater, 2013]

Sulfonamides are one typical antibiotic which is an emerging hazardous material to the ecological stability due to their continuously application and biological effects to non-target organisms. The parent-progeny transgenerational effects need investigations to indicate their long-term consequences. Currently, we tested the transgenerational effects of sulfadiazine (SD), sulfapyridine (SP) and sulfamethazine (SMZ) on L3 larva of Caenorhabditis elegans. The nematodes were exposed to aqueous sulfonamides at micromolar concentrations for 96 h, and then the effects on the behavior and growth in the exposed parent and unexposed progeny were measured. Results showed that SD, SP and SMZ inhibited three behavior indicators including body bending frequency (BBF), reversal movement (RM) and Omega turn (OT), and the growth indicator (body length, BL). Behavior indicators showed higher sensitivities than the growth indicator, and BBF had the highest sensitivity among the behavior indicators. Moreover, the effects of sulfonamides were also observed in the unexposed progeny with partially rescued or more severe inhibitions on the indicators. The behavior also showed higher sensitivity than the growth in the progeny. The transgenerational effects of sulfonamides indicated that parental exposure can multiply the harmful effects of antibiotic pollution in following generations and their potential ecological risks at environmental concentrations were further raised.

Rosas PC et al. (2016) PLoS One "Hsp72 (HSPA1A) Prevents Human Islet Amyloid Polypeptide Aggregation and Toxicity: A New Approach for Type 2 Diabetes Treatment."

Kaur P, Rosas PC, Wickman G, Panossian A, Al-Khamis FA, Nagaraja GM, Garcia LR, Asea AA

[PLoS One, 2016]

Type 2 diabetes is a growing public health concern and accounts for approximately 90% of all the cases of diabetes. Besides insulin resistance, type 2 diabetes is characterized by a deficit in -cell mass as a result of misfolded human islet amyloid polypeptide (h-IAPP) which forms toxic aggregates that destroy pancreatic -cells. Heat shock proteins (HSP) play an important role in combating the unwanted self-association of unfolded proteins. We hypothesized that Hsp72 (HSPA1A) prevents h-IAPP aggregation and toxicity. In this study, we demonstrated that thermal stress significantly up-regulates the intracellular expression of Hsp72, and prevents h-IAPP toxicity against pancreatic -cells. Moreover, Hsp72 (HSPA1A) overexpression in pancreatic -cells ameliorates h-IAPP toxicity. To test the hypothesis that Hsp72 (HSPA1A) prevents aggregation and fibril formation, we established a novel C. elegans model that expresses the highly amyloidogenic human pro-IAPP (h-proIAPP) that is implicated in amyloid formation and -cell toxicity. We demonstrated that h-proIAPP expression in body-wall muscles, pharynx and neurons adversely affects C. elegans development. In addition, we demonstrated that h-proIAPP forms insoluble aggregates and that the co-expression of h-Hsp72 in our h-proIAPP C. elegans model, increases h-proIAPP solubility. Furthermore, treatment of transgenic h-proIAPP C. elegans with ADAPT-232, known to induce the expression and release of Hsp72 (HSPA1A), significantly improved the growth retardation phenotype of transgenic worms. Taken together, this study identifies Hsp72 (HSPA1A) as a potential treatment to prevent -cell mass decline in type 2 diabetic patients and establishes for the first time a novel in vivo model that can be used to select compounds that attenuate h-proIAPP aggregation and toxicity.