Baltaci, O. et al. (2019) International Worm Meeting "A non-canonical TGF-beta pathway drives neuronal guidance."

Snieckute, G., Haas, M., Baltaci, O., Pocock, R.

[International Worm Meeting, 2019]

Correct development of biological systems requires strict regulation of cellular processes such as cell migration, proliferation and differentiation. The transforming growth factor beta (TGF-?) pathway is a major player in these processes, however its role in neuronal migration and axon guidance is not fully understood. We discovered that SMA-6, a TGF-? receptor type I homologue in Caenorhabditis elegans acts from the hypodermis to control neuronal migration and axon guidance of the hermaphrodite-specific neurons (HSNs). Conversely, DAF-4 which is the sole TGF-? receptor type II homologue is not required for HSN development. In the canonical TGF-? pathway, the type I receptor requires phosphorylation by the type II receptor in order to function. However, we show that a TGF-? receptor type I can act independently of a TGF-? type II receptor in neuronal development, and hence identify a non-canonical mode of action. We also found that TIG-2, the human bone morphogenetic protein-7 (BMP7) homologue, binds to and functions genetically upstream of SMA-6 to direct HSN guidance. Further, the SMAD transcription factors, SMA-2, SMA-3 and SMA-4, act downstream of SMA-6 to regulate HSN development. To identify TGF-? pathway target genes important for regulating HSN development, we conducted RNA sequencing to compare the transcriptomes of wild-type, sma-6 and sma-3 mutants. Differential expression analysis identified 13 candidate genes some of which have SMAD binding sites. Finally, we found that manipulation of specific candidate SMAD target genes supress HSN developmental defects in sma-3 mutant animals, suggesting the mechanism through which TGF-? signalling regulates neuronal guidance.

Baltaci O et al. (2022) iScience "Atypical TGF-β signaling controls neuronal guidance in Caenorhabditis elegans"

Snieckute G, Archer S, Cao W, Handley A, Sherry T, Haas M, Pocock R, Pedersen ME, Baltaci O

[iScience, 2022]

Coordinated expression of cell adhesion and signaling molecules is crucial for brain development. Here, we report that the Caenorhabditis elegans transforming growth factor β (TGF-β) type I receptor SMA-6 (small-6) acts independently of its cognate TGF-β type II receptor DAF-4 (dauer formation-defective-4) to control neuronal guidance. SMA-6 directs neuronal development from the hypodermis through interactions with three, orphan, TGF-β ligands. Intracellular signaling downstream of SMA-6 limits expression of NLR-1, an essential Neurexin-like cell adhesion receptor, to enable neuronal guidance. Together, our data identify an atypical TGF-β-mediated regulatory mechanism to ensure correct neuronal development.

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 μg/mL for 24 h exposure on Caenorhabditis elegans (C. elegans), while 100 μg/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 μg/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 μg/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).

Wells L et al. (2001) Science "Glycosylation of nucleocytoplasmic proteins: signal transduction and O-GlcNAc."

Hart GW, Wells L, Vosseller K

[Science, 2001]

The dynamic glycosylation of serine or threonine residues on nuclear and cytosolic proteins by O-linked beta-N-acetylglucosamine (O-GlcNAc) is abundant in all multicellular eukaryotes. On several proteins, O-GlcNAc and O-phosphate alternatively occupy the same or adjacent sites, leading to the hypothesis that one function of this saccharide is to transiently block phosphorylation. The diversity of proteins modified by O-GlcNAc implies its importance in many basic cellular and disease processes. Here we systematically examine the current data implicating O-GlcNAc as a regulatory modification important to signal transduction cascades.

Wang, Peng et al. (2011) International Worm Meeting "Caenorhabditis elegans O-GlcNAc cycling mutants alter the proteotoxicity of models of human neurodegenerative disorders."

Forsythe, Michele, Wang, Peng, Lazarus, Brooke, Hanover, John, Love, Dona, Krause, Michael

[International Worm Meeting, 2011]

O-linked N-acetylglucosamine (O-GlcNAc) addition is an important post-translational modification that occurs on hundreds of proteins, including nuclear pore proteins, transcription factors, proteasome components and neuronal proteins. O-GlcNAc can be added onto and removed from serine or threonine residue by two evolutionally conserved enzymes: O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. O-GlcNAcylation is abundant in the brain and it has been linked to human neurodegenerative disease. We have exploited viable null alleles of the enzymes of O-GlcNAc cycling to examine the role of O-GlcNAcylation in well-characterized C. elegans models of neurodegenerative proteotoxicity. O-GlcNAc cycling dramatically modulated the severity of the proteotoxic phenotype in transgenic models of tauopathy, b-amyloid peptide and polyglutamine expansion. Intriguingly, loss-of-function of OGT alleviated, while loss of OGA enhanced these proteotoxicity phenotype. Consistent with these observations, the O-GlcNAc cycling mutants exhibit altered stress responses and changes in the protein degradation machinery. These findings suggest that modulators of O-GlcNAc cycling may prove useful for anti-neurodegenerative disease therapies.

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.