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Rana, Mainpal et al. (2015) International Worm Meeting "A Novel Pathway for Germ Cell Differentiation in C. elegans."

Rana, Mainpal, Nance, Jeremy, Yanowitz, Judith

[

International Worm Meeting,

2015]

Despite the central importance of germ cells for the transmission of genetic material between generations, our understanding of the molecular programs that control primordial germ cell (PGC) specification and differentiation are limited. Here we present our studies that xnd-1 (X nondisjunction factor-1), which we previously showed has a role in regulating meiotic crossover formation, is also an early determinant of germ cell fates. Maternal XND-1 protein first appears in the P4 germline blastomere where it is required to ensure the division into the PGCs, Z2 and Z3. Hence, xnd-1 mutant embryos display a novel "one PGC" phenotype due to G2 arrest of P4. Zygotic XND-1 comes at on at the ~250 cell stage making it the earliest PGC marker in the worm. This protein then dictates the ultimate size of the germline. Based on similar expression patterns and phenotypes, we explored xnd-1's epistatic relationships with the Nanos homologs, nos-1 and nos-2. Double mutants display synthetic sterility with nearly half of the animals developing without a germ line. Further removal of nos-1 leads to almost complete sterility, and the vast majority of animals develop without germ cells. The sterility in xnd-1 and the double and triple mutants is preceded by an increase within the PGCs of the transcription-associated activating histone mark, H3K4me2. These data strongly suggest that xnd-1 defines a new branch for PGC development that functions redundantly with nos-2 and nos-1 to promote germ line fates by maintaining transcriptional quiescence and regulating germ cell proliferation. .

Amini, Rana et al. (2013) International Worm Meeting "Anillin promotes syncytial organization and maintenance of the C. elegans germline."

Maddox, Amy S., Zetka, Monique, Labella, Sara, Chartier, Nicolas T., Amini, Rana, Labbe, Jean-Claude

[

International Worm Meeting,

2013]

Cytokinesis, the last step of cell division, is required for the physical separation of the two daughter cells. During certain developmental stages however, incomplete cytokinesis gives rise to interconnected cells, forming a syncytium. The C. elegans adult germline is a syncytial organ enriched in ANI-2, a short homolog of the conserved scaffolding protein anillin, which controls cytokinesis. ANI-2 is present from the onset of germ cell specification and is enriched in intercellular syncytial bridges, suggesting that it might promote germline syncytium formation in C. elegans. To investigate this possibility, we developed a light microscopy-based assay to analyze the timing of syncytium formation during gonad development. We found that syncytial organization of the germline occurs progressively during larval development and completes shortly before animals enter the adult stage. Interestingly, while the germline of ani-2(-/-) mutants lacks defined syncytial openings, gonad development proceeds normally until animals reach the adult stage, when cytoplasmic partitions regress and germ cells progressively become polynucleated. This stage of gonad development is characterized by the initiation of cytoplasmic flows that promote oocyte growth, suggesting that ANI-2 is required to stabilize intercellular bridges when these flows initiate. In support of this, we did not observe severe multinucleation in male gonads or in tumorous germlines, which both lack cytoplasmic flows. Furthermore, time-lapse analysis of the proximal gonad at fertilization revealed that ANI-2 could confer elastic-like properties to the gonad, indicating that it can compensate for mechanical stress. We propose a model in which ANI-2 is required to promote syncytial organization of the germline and that its presence becomes essential to compensate for the mechanical stress resulting from cytoplasmic flows at the onset of oogenesis.

Amini, Rana et al. (2015) International Worm Meeting "Biogenesis in the C. elegans germline syncytium: from nucleation to maturation ."

Labbe, Jean-Claude, Amini, Rana, St-Pierre-See, Alexandre

[

International Worm Meeting,

2015]

Cytokinesis consists in the physical separation of the two daughter cells, after mitosis. However, during development of certain tissues, mitotic division is followed by incomplete cytokinesis, giving rise to interconnected cells in a shared cytoplasm, or syncytium. Syncytial structures have been repeatedly described in female and male germlines in species ranging from insects to humans. Nevertheless, the mechanism of syncytium formation is poorly characterized. To understand this, we studied the syncytial C. elegans germline wherein germ cells (GCs) remain connected via stable intercellular bridges, also known as GC bridges. Using live-cell imaging, we found that ANI-1, ANI-2, NMY-2, UNC-59Septin, CYK-7 (a novel midbody component), ZEN-4Mklp1 are all stable components of GC bridges while RHO-1RhoA and ECT-2RhoGEF have a cortical localization throughout germline development from the L1 stage to adulthood. All GCs originate from the germline blastomere P4 that divides into the two primordial germ cells (PGCs) during embryogenesis. To understand the mechanism of syncytium formation, we monitored the dynamics of P4 cytokinesis. We found that P4, similar to its somatic neighbors, goes normally through the first phase of cytokinesis, also known as cytoplasmic isolation. Interestingly however, unlike somatic blastomeres, P4 fails to complete the second phase of cytokinesis wherein the midbody (MB) is released from the cell-cell boundary. While the MBs of somatic cells disappear soon after their cortical release, the MB connecting the two PGCs remains tightly associated to the cortex throughout embryogenesis. Our findings support a model in which incomplete cytokinesis of the P4 blastomere results in persistence of the MB between the two PGCs, thus forming a stable bridge that, in turn, promotes syncytium biogenesis.

Rana, Mainpal et al. (2013) International Worm Meeting "Multiple Aspects of C. elegans Germ Cell Development are Regulated by XND-1."

Rana, Mainpal, Yanowitz, Judith

[

International Worm Meeting,

2013]

Despite the central importance of germ cells for the transmission of genetic material between generations, very little is known about the molecular programs that regulate their development. Defects during germ cell formation and differentiation can lead to infertility, birth defects, and formation of germ cell cancers. Work in our lab has identified xnd-1 (X nondisjunction factor-1) as a key regulator of germ cell development in the nematode, Caenorhabditis elegans. Our analysis has revealed that xnd-1 is one of the first genes turned on in the primordial germ cells (PGC) suggesting it may be a key regulator of PGC development. Consistent with this hypothesis, xnd-1 mutant embryos exhibit multiple defects in PGC development including aberrant PGCs number and size, mislocalization, premature proliferation and missegregation of P-granules. Furthermore, co-depletion of XND-1 and NOS-2, a C. elegans Nanos homolog important for PGC development, reveals a synthetic sterile phenotype. The sterility is specific to nos-2, as it is not seen in nos-1 or nos-3 double mutants. These results suggest that xnd-1 and nos-2 function in parallel pathways for germline specification. Using time lapse imaging, we are exploring the causes and consequences of the PGC defects. We have also identified key embryonic regulations affecting XND-1 expression in the PGC.

Rana M et al. (2024) MicroPubl Biol "oxi-1 is required for chemotaxis to odorants sensed by AWA but not AWC neurons."

Kowalski J, Rana M

[

MicroPubl Biol,

2024]

This study examines the role of the oxi-1 UBE3B gene in chemotaxis of C. elegans to volatile odorants. Compared to wild type worms, oxi-1 mutants showed no difference in chemotaxis to the AWC-specific odorant, isoamyl alcohol but a significant decrease in chemotaxis compared to odr-7 mutants. Both oxi-1 and odr-7 mutants exhibited significant decreases in chemotaxis to AWA-specific odorants, pyrazine and diacetyl. For thiazole, which is sensed by both AWA and AWC neurons, only odr-7 mutants showed significantly decreased chemotaxis. These data demonstrate oxi-1 is required for chemotaxis to AWA- but not AWC-specific odorants, the mechanisms of which should be investigated.

Rana AK et al. (2013) Antimicrob Agents Chemother "Molecular characterization of an rsmD-like rRNA methyltransferase from the Wolbachia endosymbiont of Brugia malayi and antifilarial activity of specific inhibitors of the enzyme."

Rana AK, Siddiqi MI, Chandra S, Misra-Bhattacharya S

[

Antimicrob Agents Chemother,

2013]

The endosymbiotic organism Wolbachia is an attractive antifilarial drug target. Here we report on the cloning and expression of an rsmD-like rRNA methyltransferase from the Wolbachia endosymbiont of Brugia malayi, its molecular properties, and assays for specific inhibitors. The gene was found to be expressed in all the major life stages of B. malayi. The purified enzyme expressed in Escherichia coli was found to be in monomer form in its native state. The activities of the specific inhibitors (heteroaryl compounds) against the enzyme were tested with B. malayi adult and microfilariae for 7 days in vitro at various concentrations, and NSC-659390 proved to be the most potent compound (50% inhibitory concentration [IC50], 0.32 M), followed by NSC-658343 (IC50, 4.13 M) and NSC-657589 (IC50, 7.5 M). On intraperitoneal administration at 5 mg/kg of body weight for 7 days to adult jirds into which B. malayi had been transplanted intraperitoneally, all the compounds killed a significant proportion of the implanted worms. A very similar result was observed in infected mastomys when inhibitors were administered. Docking studies of enzyme and inhibitors and an in vitro tryptophan quenching experiment were also performed to understand the binding mode and affinity. The specific inhibitors of the enzyme showed a higher affinity for the catalytic site of the enzyme than the nonspecific inhibitors and were found to be potent enough to kill the worm (both adults and microfilariae) in vitro as well as in vivo in a matter of days at micromolar concentrations. The findings suggest that these compounds be evaluated against other pathogens possessing a methyltransferase with a DPPY motif and warrant the design and synthesis of more such inhibitors.

Ji F et al. (2024) Sci Rep "Antimicrobial peptide 2K4L inhibits the inflammatory response in macrophages and Caenorhabditis elegans and protects against LPS-induced septic shock in mice."

Ji F, Shang D, Tian G

[

Sci Rep,

2024]

2K4L is a rationally designed analog of the short α-helical peptide temporin-1CEc, a natural peptide isolated and purified from the skin secretions of the Chinese brown frog Rana chensinensis by substituting amino acid residues. 2K4L displayed improved and broad-spectrum antibacterial activity than temporin-1CEc in vitro. Here, the antibacterial and anti-inflammatory activities of 2K4L in macrophages, C. elegans and mice were investigated. The results demonstrated that 2K4L could enter THP-1 cells to kill a multidrug-resistant Acinetobacter baumannii strain (MRAB 0227) and a sensitive A. baumannii strain (AB 22933), as well as reduce proinflammatory responses induced by MRAB 0227 by inhibiting NF-κB signaling pathway. Similarly, 2K4L exhibited strong bactericidal activity against A. baumannii uptake into C. elegans, extending the lifespan and healthspan of the nematodes. Meanwhile, 2K4L alleviated the oxidative stress response by inhibiting the expression of core genes in the p38 MAPK/PMK-1 signaling pathway and downregulating the phosphorylation level of p38, thereby protecting the nematodes from damage by A. baumannii. Finally, in an LPS-induced septic model, 2K4L enhanced the survival of septic mice and decreased the production of proinflammatory cytokines by inhibiting the signaling protein expression of the MAPK and NF-κB signaling pathways and protecting LPS-induced septic mice from a lethal inflammatory response. In conclusion, 2K4L ameliorated LPS-induced inflammation both in vitro and in vivo.

Foguth R et al. (2020) Toxics "Per- and Polyfluoroalkyl Substances (PFAS) Neurotoxicity in Sentinel and Non-Traditional Laboratory Model Systems: Potential Utility in Predicting Adverse Outcomes in Human Health."

Foguth R, Cannon J, Sepulveda MS

[

Toxics,

2020]

Per- and polyfluoroalkyl substances (PFAS) are a class of chemicals that were widely used in manufacturing and are now present in the environment throughout the world. It is known that various PFAS are quantifiable in human in blood, but potential adverse health outcomes remain unclear. Sentinel and non-traditional model species are useful to study potential toxicity of PFAS in order to understand the relationship between environmental and human health. Here, we present a critical review of studies on the neurotoxicity of PFAS in sentinel and non-traditional laboratory model systems, including Caenorhabditis elegans (nematode), Dugesia japonica (planarian), Rana pipiens (frogs), Danio rerio and Oryzias melastigma (fish), and Ursus maritimus (polar bears). PFAS have been implicated in developmental neurotoxicity in non-traditional and traditional model systems as well as sentinel species, including effects on neurotransmitter levels, especially acetylcholine and its metabolism. However, further research on the mechanisms of toxicity needs to be conducted to determine if these chemicals are affecting organisms in a similar manner. Overall, findings tend to be similar among the various species, but bioaccumulation may vary, which needs to be taken into account in future studies by quantifying target organ concentrations of PFAS to better compare different species. Furthermore, data on the majority of PFAS is lacking in neurotoxicity testing, and additional studies are needed to corroborate findings thus far.

Hermes-Lima M et al. (2002) Comp Biochem Physiol C Toxicol Pharmacol "Animal response to drastic changes in oxygen availability and physiological oxidative stress."

Zenteno-Savi\;n T, Hermes-Lima M

[

Comp Biochem Physiol C Toxicol Pharmacol,

2002]

Oxygen is essential for most life forms, but it is also inherently toxic due to its biotransformation into reactive oxygen species (ROS). In fact, the development of many animal and plant pathological conditions, as well as natural aging, is associated with excessive ROS production and/or decreased antioxidant capacity. However, a number of animal species are able to tolerate, under natural conditions, situations posing a large potential for oxidative stress. Situations range from anoxia in fish, frogs and turtles, to severe hypoxia in organs of freeze-tolerant snakes, frogs and insect larvae, or diving seals and turtles, and mild hypoxia in organs of dehydrated frogs and toads or estivating snails. All situations are reminiscent of ischemia/reperfusion events that are highly damaging to most mammals and birds. This article reviews the responses of anoxia/hypoxia-tolerant animals when subjected to environmental and metabolic stresses leading to oxygen limitation. Abrupt changes in metabolic rate in ground squirrels arousing from hibernation, as well as snails arousing from estivation, may also set up a condition of increased ROS formation. Comparing the responses from these diverse animals, certain patterns emerge. The most commonly observed response is an enhancement of the antioxidant defense. The increase in the baseline activity of key antioxidant enzymes, as well as ''secondary'' enzymatic defenses, and/or glutathione levels in preparation for a putative oxidative stressful situation arising from tissue reoxygenation seem to be the preferred evolutionary adaptation. Increasing the overall antioxidant capacity during anoxia/hypoxia is of relevance for species such as garter snakes (Thamnophis sirtalis parietalis) and wood fogs (Rana sylvatica), while diving freshwater turtles (Trachemys scripta elegans) appear to rely mainly upon high constitutive activities of antioxidant enzymes to deal with oxidative stress arising during tissue reoxygenation. The possibility that some animal species might control post-anoxic ROS generation cannot be excluded.

Seitan VC et al. (2006) PLoS Biol "Metazoan Scc4 homologs link sister chromatid cohesion to cell and axon migration guidance."

Banks P, Strachan T, Rana A, Newbury SF, Bateman A, Dorsett D, Benard CY, Tempst P, Seitan VC, Hostert A, Krpic S, Laval S, Hekimi S, Majid NA, Rollins RA, Erdjument-Bromage H, Smith J

[

PLoS Biol,

2006]

Saccharomyces cerevisiae Scc2 binds Scc4 to form an essential complex that loads cohesin onto chromosomes. The prevalence of Scc2 orthologs in eukaryotes emphasizes a conserved role in regulating sister chromatid cohesion, but homologs of Scc4 have not hitherto been identified outside certain fungi. Some metazoan orthologs of Scc2 were initially identified as developmental gene regulators, such as Drosophila Nipped-B, a regulator of cut and Ultrabithorax, and delangin, a protein mutant in Cornelia de Lange syndrome. We show that delangin and Nipped-B bind previously unstudied human and fly orthologs of Caenorhabditis elegans MAU-2, a non-axis-specific guidance factor for migrating cells and axons. PSI-BLAST shows that Scc4 is evolutionarily related to metazoan MAU-2 sequences, with the greatest homology evident in a short N-terminal domain, and protein-protein interaction studies map the site of interaction between delangin and human MAU-2 to the N-terminal regions of both proteins. Short interfering RNA knockdown of human MAU-2 in HeLa cells resulted in precocious sister chromatid separation and in impaired loading of cohesin onto chromatin, indicating that it is functionally related to Scc4, and RNAi analyses show that MAU-2 regulates chromosome segregation in C. elegans embryos. Using antisense morpholino oligonucleotides to knock down Xenopus tropicalis delangin or MAU-2 in early embryos produced similar patterns of retarded growth and developmental defects. Our data show that sister chromatid cohesion in metazoans involves the formation of a complex similar to the Scc2-Scc4 interaction in the budding yeast. The very high degree of sequence conservation between Scc4 homologs in complex metazoans is consistent with increased selection pressure to conserve additional essential functions, such as regulation of cell and axon migration during development.

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