Ilbay O et al. (2019) Curr Biol "Pheromones and Nutritional Signals Regulate the Developmental Reliance on let-7 Family MicroRNAs in C.elegans."

Ambros V, Ilbay O

[Curr Biol, 2019]

Adverse environmental conditions can affect rates ofanimal developmental progression and lead to temporary developmental quiescence (diapause), exemplified by the dauer larva stage of the nematode Caenorhabditis elegans (C.elegans). Remarkably, patterns of cell division and temporal cell-fate progression in C.elegans larvae are not affected by changes in developmental trajectory. However, the underlying physiological and gene regulatory mechanisms that ensure robust developmental patterning despite substantial plasticity in developmental progression are largely unknown. Here, we report thatdiapause-inducing pheromones correct heterochronic developmental cell lineage defects caused by insufficient expression of let-7 family microRNAs in C.elegans. Moreover, two conserved endocrine signaling pathways, DAF-7/TGF- and DAF-2/Insulin, that confer on the larva diapause and non-diapause alternative developmental trajectories interact with the nuclear hormone receptor, DAF-12, to initiate and regulate a rewiring of the genetic circuitry controlling temporal cell fates. This rewiring includes engagement of certain heterochronic genes, lin-46, lin-4, and nhl-2, that are previously associated with an altered genetic program in post-diapause animals, in combination with a novel ligand-independent DAF-12 activity, to downregulate the critical let-7 family target Hunchback-like-1 (HBL-1). Our results show how pheromone or endocrine signaling pathways can coordinately regulate both developmental progression and cell-fate transitions in C.elegans larvae under stress so that the developmental schedule of cell fates remains unaffected by changes in developmental trajectory.

Ilbay O et al. (2019) Development "Regulation of nuclear-cytoplasmic partitioning by the lin-28-lin-46 pathway reinforces microRNA repression of HBL-1 to confer robust cell-fate progression in C. elegans."

Ambros V, Ilbay O

[Development, 2019]

MicroRNAs target complementary mRNAs for degradation or translational repression, reducing or preventing protein synthesis. In <i>C. elegans</i>, the transcription factor HBL-1 (Hunchback-like 1) promotes early larval (L2) stage cell-fates, and the <i>let-7-</i>family microRNAs temporally down-regulate HBL-1 to enable the L2-to-L3 cell-fate progression. In parallel to <i>let-7</i>-family microRNAs, the conserved RNA binding protein LIN-28 and its downstream gene <i>lin-46</i>, also act upstream of HBL-1 in regulating the L2-to-L3 cell-fate progression. The molecular function of LIN-46, and how the <i>lin-28-lin-46</i> pathway regulates HBL-1, are not understood. Here, we report that the regulation of HBL-1 by the <i>lin-28-lin-46</i> pathway is independent of the <i>let-7</i>/<i>lin-4</i> microRNA complementary sites (LCSs) in the <i>hbl-1</i> 3'UTR, and involves a stage-specific post-translational regulation of HBL-1 nuclear accumulation. We find that LIN-46 is necessary and sufficient to prevent nuclear accumulation of HBL-1. Our results illuminate that the robust progression from L2 to L3 cell-fates depends on the combination of two distinct modes of HBL-1 down-regulation: decreased synthesis of HBL-1 via <i>let-7</i>-family microRNA activity, and decreased nuclear accumulation of HBL-1 via action of the <i>lin-28</i>-<i>lin-46</i> pathway.

Ilbay O et al. (2021) Cell Rep "C.elegans LIN-28 controls temporal cell fate progression by regulating LIN-46 expression via the 5' UTR of lin-46 mRNA."

Nelson C, Ilbay O, Ambros V

[Cell Rep, 2021]

Lin28/LIN-28 is a conserved RNA-binding protein that promotes proliferation and pluripotency and can be oncogenic in mammals. Mammalian Lin28 and C.elegans LIN-28 have been shown to inhibit biogenesis of the conserved cellular differentiation-promoting microRNA let-7 by directly binding to unprocessed let-7 transcripts. Lin28/LIN-28 also bind and regulate many mRNAs in diverse cell types. However, the determinants and consequences of LIN-28-mRNA interactions are not well understood. Here, we report that C.elegans LIN-28 represses the expression of LIN-46, a downstream protein in the heterochronic pathway. We find that lin-28 and sequences within the lin-46 5' UTR are required to prevent LIN-46 expression at early larval stages. Moreover, we find that precocious LIN-46 expression caused by mutations in the lin-46 5' UTR is sufficient to cause precocious heterochronic defects similar to those of lin-28(lf) animals. Thus, our findings demonstrate the biological importance of the regulation of individual target mRNAs by LIN-28.

Franz M et al. (1987) Parasitol Res "Electron-microscopic observations on the female worms of six Onchocerca species from cattle and red deer."

Copeman DB, Franz M, Schulz-Key H

[Parasitol Res, 1987]

The midbody regions of female worms of six Onchocerca species (O. flexuosa, O. tarsicola, O. lienalis, O. gutturosa, O. armillata, O. gibsoni) were studied by transmission electron microscopy. The cuticular layering was rather similar in all species with the ridges built up by the cortical layers and the inner cuticular striations by the median or basal layers. Differences in the epicuticular morphology were considerable. O. flexuosa and O. lienalis had a thin epicuticle without protuberances, the epicuticle of O. armillata carried small knobs, and O. tarsicola, O. gutturosa, and O. gibsoni had a thick trilaminar epicuticle with long protuberances. Extreme hypertrophy of hypodermis and reductions of somatic musculature were observed in O. flexuosa and O. gibsoni. Less extended thickenings of the hypodermis were observed in the other species. No degenerative alterations were found in the muscle cells of O. gutturosa and O. lienalis. The intestinal lumen of most of the species was in a central position, but in O. tarsicola and O. gibsoni the lumen was reduced to small clefts between the intestinal cells. In these species, numerous electron-dense, concentric granules were observed in the cytoplasm of the intestinal cells. The proportions of the various organs differed considerably from species to species, e.g., the uteri contained the embryos filed one behind the other in O. tarsicola, whereas 50 or more embryos were found beside one another in cross-sections of the uterus of O. gibsoni. The comparative study showed that O. gibsoni and O. volvulus have many derived morphological characteristics in common and that in the other species more primitive stages of development of these morphological marks can be observed.

Zhang S et al. (2021) Environ Pollut "Responses of Caenorhabditis elegans to various surface modifications of alumina nanoparticles"

Zhang Z, Xu Y, Mao X, Chu Q, Zhang S, Zhang M

[Environ Pollut, 2021]

The surface modifications of nanoparticles (NPs), are well-recognized parameters that affect the toxicity, while there has no study on toxicity of Al(2)O(3) NPs with different surface modification. Therefore, for the first time, this study pays attention to evaluating the toxicity and potential mechanism of pristine Al(2)O(3) NPs (p-Al(2)O(3)), hydrophilic (w-Al(2)O(3)) and lipophilic (o-Al(2)O(3)) modifications of Al(2)O(3) NPs both in vitro and in vivo. Applied concentrations of 10, 20, 40, 80,100 and 200 &#956;g/mL for 24 h exposure on Caenorhabditis elegans (C. elegans), while 100 &#956;g/mL of Al(2)O(3) NPs significantly decreased the survival rate. Using multiple toxicological endpoints, we found that o-Al(2)O(3) NPs (100 &#956;g/mL) could induce more severe toxicity than p-Al(2)O(3) and w-Al(2)O(3) NPs. After uptake by C. elegans, o-Al(2)O(3) NPs increased the intestinal permeability, easily swallow and further destroy the intestinal membrane cells. Besides, cytotoxicity evaluation revealed that o-Al(2)O(3) NPs (100 &#956;g/mL) are more toxic than p-Al(2)O(3) and w-Al(2)O(3). Once inside the cell, o-Al(2)O(3) NPs could attack mitochondria and induce the over-production of reactive oxygen species (ROS), which destroy the intracellular redox balance and lead to apoptosis. Furthermore, the transcriptome sequencing and RT-qPCR data also demonstrated that the toxicity of o-Al(2)O(3) NPs is highly related to the damage of cell membrane and the imbalance of intracellular redox. Generally, our study has offered a comprehensive sight to the adverse effects of different surface modifications of Al(2)O(3) NPs on environmental organisms and the possible underlying mechanisms.

Bain O et al. Ann Parasitol Hum Comp "[Redescription of Onchocerca gibsoni C. et J., 1910 (author's transl)]."

Bain O, Beveridge I

[Ann Parasitol Hum Comp]

O. gibsoni is redescribed; the hypoderma and the musculature of the female body are studied on transversal sections and compared to several other species of Onchocerca. These structures and the general morphology show the autonomy of a small line of asiatic and african Onchocerca of Bovines (O. gibsoni, O. dukei, O. ochengi and, probably, the other nodular Onchocerca of Bovinae), to which the human parasite, O. volvulus, belongs. The presence of O. gibsoni in Africa is doubtful.

Wang P et al. (2012) Proc Natl Acad Sci U S A "O-GlcNAc cycling mutants modulate proteotoxicity in Caenorhabditis elegans models of human neurodegenerative diseases."

Love DC, Wang P, Hanover JA, Krause MW, Lazarus BD, Forsythe ME

[Proc Natl Acad Sci U S A, 2012]

O-GlcNAcylation is an abundant posttranslational modification in the brain implicated in human neurodegenerative diseases. We have exploited viable null alleles of the enzymes of O-GlcNAc cycling to examine the role of O-GlcNAcylation in well-characterized Caenorhabditis elegans models of neurodegenerative proteotoxicity. O-GlcNAc cycling dramatically modulated the severity of the phenotype in transgenic models of tauopathy, amyloid -peptide, and polyglutamine expansion. Intriguingly, loss of function of O-GlcNAc transferase alleviated, whereas loss of O-GlcNAcase enhanced, the phenotype of multiple neurodegenerative disease models. The O-GlcNAc cycling mutants act in part by altering DAF-16-dependent transcription and modulating the protein degradation machinery. These findings suggest that O-GlcNAc levels may directly influence neurodegenerative disease progression, thus making the enzymes of O-GlcNAc cycling attractive targets for neurodegenerative disease therapies.

Cheung BHH et al. (2005) Curr Biol "Experience-dependent modulation of C. elegans behavior by ambient oxygen."

Cohen M, Rogers C, Cheung BHH, De Bono M, Albayram O

[Curr Biol, 2005]

Background: Ambient oxygen (O(2)) influences the behavior of organisms from bacteria to man. In C. elegans, an atypical O(2) binding soluble guanylate cyclase (sGC), GCY-35, regulates O(2) responses. However, how acute and chronic changes in O(2) modify behavior is poorly understood. Results: Aggregating C. elegans strains can respond to a reduction in ambient O(2) by a rapid, reversible, and graded inhibition of roaming behavior. This aerokinetic response is mediated by GCY-35 and GCY-36 sGCs, which appear to become activated as O(2) levels drop and to depolarize the AQR, PQR, and URX neurons. Coexpression of GCY-35 and GCY-36 is sufficient to transform olfactory neurons into O(2) sensors. Natural variation at the npr-1 neuropeptide receptor alters both food-sensing and O(2)-sensing circuits to reconfigure the salient features of the C. elegans environment. When cultivated in 1% O(2) for a few hours, C. elegans reset their preferred ambient O(2), seeking instead of avoiding 0%-5% O(2). This plasticity involves reprogramming the AQR, PQR, and URX neurons. Conclusions: To navigate O(2) gradients, C. elegans can modulate turning rates and speed of movement. Aerotaxis can be reprogrammed by experience or engineered artificially. We propose a model in which prolonged activation of the AQR, PQR, and URX neurons by low O(2) switches on previously inactive O(2) sensors. This enables aerotaxis to low O(2) environments and may encode a "memory" of previous cultivation in low O(2).

Dong DL et al. (1994) J Biol Chem "Purification and characterization of an O-GlcNAc selective N-acetyl-beta-D-glucosaminidase from rat spleen cytosol."

Hart GW, Dong DL

[J Biol Chem, 1994]

Glycosylation of nuclear and cytoplasmic proteins by O-linked N-acetylglucosamine (O-GlcNAc) monosaccharides is an abundant, ubiquitous, and transient post-translational modification. To characterize enzymes involved in removal of these sugars, a neutral and cytoplasmic N-acetyl-beta-D-glucosaminidase (O-GlcNAcase) with strong selectivity for O-GlcNAc-synthetic glycopeptides has been purified over 22,000-fold from rat spleen homogenate. The purified O-GlcNAcase has two major polypeptides of apparent M(r) = 54,000 (alpha subunit) and M(r) = 51,000 (beta subunit). Enzyme activity sediments at M(r) = 106,000 on sucrose gradients, indicating that the native O-GlcNAcase is an alpha beta heterodimer. The O-GlcNAcase also shows substantially stronger relative activity against O-GlcNAc-synthetic glycopeptides than other hexosaminidases. Unlike acidic lysosomal hexosaminidases, O-GlcNAcase is not inhibited by GalNAc or its analogs, has no other detectable glycosidase activities, and does not cross-react with antibodies against acidic hexosaminidases. Subcellular fractionation and latency studies demonstrate the cytoplasmic and nucleoplasmic localization of the enzyme and its ubiquitous presence in tissues. These studies suggest that O-GlcNAcase is involved in the regulated removal of O-GlcNAc from O-GlcNAc-bearing glycoproteins in the nucleoplasmic and cytoplasmic compartments of cells.

Wells L et al. (2002) J Biol Chem "Dynamic O-glycosylation of nuclear and cytosolic proteins: further characterization of the nucleocytoplasmic beta-N-acetylglucosaminidase, O-GlcNAcase."

Hart GW, Chen C, Wells L, Gao Y, Mahoney JA, Vosseller K, Rosen A

[J Biol Chem, 2002]

beta-O-linked N-acetylglucosamine (O-GlcNAc) is an abundant and dynamic post-translational modification implicated in protein regulation that appears to be functionally more similar to phosphorylation than to classical glycosylation. There are nucleocytoplasmic enzymes for the attachment and removal of O-GlcNAc. Here, we further characterize the recently cloned beta-N-acetylglucosaminidase, O-GlcNAcase. Both recombinant and purified endogenous O-GlcNAcase rapidly release free GlcNAc from O-GlcNAc-modified peptide substrates. The recombinant enzyme functions as a monomer and has kinetic parameters (K(m) = 1.1 mm for paranitrophenyl-GlcNAc, k(cat) = 1 s(-1)) that are similar to those of lysosomal hexosaminidases. The endogenous O-GlcNAcase appears to be in a complex with other proteins and is predominantly localized to the cytosol. Overexpression of the enzyme in living cells results in decreased O-GlcNAc modification of nucleocytoplasmic proteins. Finally, we show that the enzyme is a substrate for caspase-3 but, surprisingly, the cleavage has no effect on in vitro O-GlcNAcase activity. These studies support the identification of this protein as an O-GlcNAcase and identify important interactions and modifications that may regulate the enzyme and O-GlcNAc cycling.