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[
International Worm Meeting,
2019]
It has recently emerged that some animals can pass on 'memory' of previous infection to their offspring, thereby enhancing immunity in their progeny. This 'inherited immunity' is an example of epigenetic inheritance, whereby the parental environment modulates the germline, without altering the DNA sequence. Though inherited immunity has been shown to provide resistance to bacterial, viral and fungal pathogens, the molecular mechanisms underlying protection are unknown. Studies in C. elegans have enabled key advances in both immunity and epigenetics. Microsporidia are poorly-characterised fungal pathogens, and Nematocida parisii is a microsporidial parasite of C. elegans. Here, we show that the progeny of N. parisii-infected worms exhibit robust immunity against microsporidia. Whilst microsporidia replicate in the intestinal cells of naive larvae and inhibit worm development, parasitism is reduced in our immune-primed larvae. These striking phenotypes make the N. parisii-C. elegans infection model an ideal system to uncover mechanisms of inherited immunity. We are now fully characterising this inherited immunity phenotype in vivo. In particular, our studies have shown that the level of immunity correlates with the strength of parental infection, lasts a single generation, and is strongest in the early larval stages of primed animals. We have also shown that immunity prevents parasite invasion of the worm intestinal cells, suggesting a protective luminal factor. We are now using gene expression analyses to reveal putative immune effectors. We are also assaying epigenetic factors to better understand the mechanism of immune transmission from parent to progeny. This study offers unique insight into the immune reactivity of the genome. Epigenetic factors mediating inherited immunity in C. elegans may have homologues in higher organisms; inherited immunity in vertebrates is unexplored and would have major implications for human health and evolution. Whilst microsporidia are important opportunistic pathogens of humans and parasitize many agriculturally important species, very little is known of their infection biology. Study of this medically and environmentally relevant pathogen will suggest new ways to treat infection.
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[
Mol Cell,
2013]
In this issue of Molecular Cell, Castellano-Pozo etal. (2013) describe a connection between R loop structures and histone 3 S10 phosphorylation (H3S10P), a mark of chromatin compaction. Their results constitute asignificant advance in our understanding of the role of R loops in genomic instability.
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[
Commun Integr Biol,
2011]
The development of bilateral symmetry during the evolution of species probably 600 million years ago brought about several important innovations: It fostered efficient locomotion, streamlining and favored the development of a central nervous system through cephalization. However, to increase their functional capacities, many organisms exhibit chirality by breaking their superficial left-right (l-r) symmetry, which manifests in the lateralization of the nervous system or the l-r asymmetry of internal organs. In most bilateria, the mechanisms that maintain consistent l-r asymmetry throughout development are poorly understood. This review highlights insights into mechanisms that couple early embryonic l-r symmetry breaking to subsequent l-r patterning in the roundworm Caenorhabditis elegans. A recently identified strategy for l-r patterning in the early C. elegans embryo is discussed, the spatial separation of midline and anteroposterior axis, which relies on a rotational cellular rearrangement and non-canonical Wnt signaling. Evidence for a general relevance of rotational/torsional rearrangements during organismal l-r patterning and for non-canonical Wnt signaling/planar cell polarity as a common signaling mechanism to maintain l-r asymmetry is presented.
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[
Zootaxa,
2022]
Rhagovelia medinae sp. nov., of the hambletoni group (angustipes complex), and R. utria sp. nov., of the hirtipes group (robusta complex), are described, illustrated, and compared with similar congeners. Based on the examination of type specimens, six new synonymies are proposed: R. elegans Uhler, 1894 = R. pediformis Padilla-Gil, 2010, syn. nov.; R. cauca Polhemus, 1997 = R. azulita Padilla-Gil, 2009, syn. nov., R. huila Padilla-Gil, 2009, syn. nov., R. oporapa Padilla-Gil, 2009, syn. nov, R. quilichaensis Padilla-Gil, 2011, syn. nov.; and R. gaigei, Drake Hussey, 1947 = R. victoria Padilla-Gil, 2012 syn. nov. The first record from Colombia is presented for R. trailii (White, 1879), and the distributions of the following species are extended in the country: R. cali Polhemus, 1997, R. castanea Gould, 1931, R. cauca Polhemus, 1997, R. gaigei Drake Hussey, 1957, R. elegans Uhler, 1894, R. femoralis Champion, 1898, R. malkini Polhemus, 1997, R. perija Polhemus, 1997, R. sinuata Gould, 1931, R. venezuelana Polhemus, 1997, R. williamsi Gould, 1931, and R. zeteki Drake, 1953.
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[
Acta Crystallogr Sect F Struct Biol Cryst Commun,
2008]
Caenorhabditis elegans expresses two manganese superoxide dismutase enzymes (MnSOD-2 and MnSOD-3) that are targeted to the mitochondrion. MnSOD-2 is constitutively expressed, while synthesis of MnSOD-3 is inducible. The structures of these two mononuclear metalloenzymes have been determined to 1.8 and 1.7 A resolution, respectively. Pink crystals formed in space group P4(1)2(1)2 for each, with unit-cell parameters a = b = 81.0, c = 137.4 A for MnSOD-2 and a = b = 81.8, c = 136.0 A for MnSOD-3. The final structure of MnSOD-3 was refined to R = 21.6% and R(free) = 26.2% at 293 K, and R = 18.9% and R(free) = 22.6% at 100 K, while that of MnSOD-2 was refined to R = 16.9% and R(free) = 20.1% at 100 K. The asymmetric unit cell is comprised of two subunits. The resulting structures are very similar to that of human MnSOD and form a tetramer corresponding to a dimer of dimers. The subunit interface between dimers is comprised of two four-helix bundles that stabilize the biologically significant homotetramer.
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[
Dev Biol,
2024]
While the nervous system of bilaterian animals is mainly left-right (L-R) symmetric at the anatomical level, some molecular and functional L-R asymmetries exist. However, the extent of these molecular asymmetries and their functional consequences remain poorly characterized. C. elegans allows to study L-R asymmetries in the nervous system with single-neuron resolution. We have previously shown that a neural bHLH transcription factor, HLH-16/Olig, is L-R asymmetrically expressed in the AIY neuron lineage and regulates AIY axon projections in a L-R asymmetric manner. Here, by combining a candidate approach and single-cell RNA sequencing data analysis, we identify the ephrin protein EFN-2 and the Flamingo protein FMI-1 as downstream targets of HLH-16 that are L-R asymmetrically expressed in the AIY lineage. We show that EFN-2 and FMI-1 collaborate in the L-R asymmetric regulation of axonal growth. EFN-2 may act via a non-canonical receptor of the L1CAM family, SAX-7. Our study reveals novel molecular L-R asymmetries in the C. elegans nervous system and their functional consequences.
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[
Mol Cell,
2013]
R loops are transcription byproducts that constitute athreat to genome integrity. Here we show that R loops are tightly linked to histone H3 S10 phosphorylation (H3S10P), a mark of chromatin condensation.Chromatin immunoprecipitation (ChIP)-on-chip (ChIP-chip) analyses reveal H3S10P accumulation at centromeres, pericentromeric chromatin, and a large number of active open reading frames (ORFs) in R-loop-accumulating yeast cells, better observed in G1. Histone H3S10 plays a key role in maintaining genome stability, as scored by ectopic recombination and plasmid loss, Rad52 foci, and Rad53 checkpoint activation. H3S10P coincides with the presence of DNA-RNA hybrids, is suppressed by ribonucleaseH overexpression, and causes reduced accessibility of restriction endonucleases, implying a tight connection between R loops, H3S10P, and chromatin compaction. Such histone modifications were also observed in R-loop-accumulating Caenorhabditis elegans and HeLa cells. We therefore provide a role of RNA in chromatin structure essential to understand how R loops modulate genome dynamics.
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[
Curr Biol,
2006]
BACKGROUND: Nervous systems are largely bilaterally symmetric on a morphological level but often display striking degrees of functional left/right (L/R) asymmetry. How L/R asymmetric functional features are superimposed onto an essentially bilaterally symmetric structure and how nervous-system laterality relates to the L/R asymmetry of internal organs are poorly understood. We address these questions here by using the establishment of L/R asymmetry in the ASE chemosensory neurons of C. elegans as a paradigm. This bilaterally symmetric neuron pair is functionally lateralized in that it senses a distinct class of chemosensory cues and expresses a putative chemoreceptor family in a L/R asymmetric manner. RESULTS: We show that the directionality of the asymmetry of the two postmitotic ASE neurons ASE left (ASEL) and ASE right (ASER) in adults is dependent on a L-/R-symmetry-breaking event at a very early embryonic stage, the six-cell stage, which also establishes the L/R asymmetric placement of internal organs. However, the L/R asymmetry of the ASE neurons per se is dependent on an even earlier anterior-posterior (A/P) Notch signal that specifies embryonic ABa/ABp blastomere identities at the four-cell stage. This Notch signal, which functions through two T box genes, acts genetically upstream of a miRNA-controlled bistable feedback loop that regulates the L/R asymmetric gene-expression program in the postmitotic ASE cells. CONCLUSIONS: Our results link adult neuronal laterality to the generation of the A/P axis at the two-cell stage and raise the possibility that neural asymmetries observed across the animal kingdom are similarly established by very early embryonic interactions.
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[
J Biol Chem,
1990]
The nematode Caenorhabditis elegans (C. elegans) expresses the regulatory subunit (R) of cAMP-dependent protein kinase at a level similar to the levels determined for R subunits in mammalian tissues. Approximately 60% of the C. elegans cAMP-binding protein is tightly associated with particulate structures by noncovalent interactions. Ionic detergents or 7 M urea solubilize particulate R. Solubilized and cytosolic R subunits have apparent Mr values of 52,000 and pI values of 5.5. cDNA and genomic DNA encoding a unique C. elegans R subunit were cloned and sequenced. The derived amino acid sequence contains 375 residues; carboxyl-terminal residues 145-375 are 69% identical with mammalian RI. However, residues 44-145 are markedly divergent from the corresponding regions of all other R sequences. This region might provide sufficient structural diversity to adapt a single R subunit for multiple functional roles in C. elegans. Antibodies directed against two epitopes in the deduced amino acid sequence of C. elegans R avidly bound nematode cytosolic and particulate R subunits on Western blots and precipitated dissociated R subunits and R2C2 complexes from solution. Immunofluorescence analysis revealed that the tip of the head, which contains chemosensory and mechanosensory neurons, and the pharyngeal nerve ring were enriched in R. The R subunit concentration is low during early embryogenesis in C. elegans. A sharp increase (approximately 6-fold) in R content begins several hours before the nematodes hatch and peaks during the first larval stage. Developmental regulation of R expression occurs at translational and/or post-translational levels. The 8-kilobase pair C. elegans R gene is divided into 8 exons by introns ranging from 46 to 4300 base pairs. The 5'-flanking region has no TATA box and contains preferred and minor transcription start sites.
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[
Cell Signal,
2013]
The cAMP-dependent protein kinase (protein kinase A, PK-A) plays a key role in the control of eukaryotic cellular activity. The enzymology of PK-A in the free-living nematode, Caenorhabditis elegans is deceptively simple. Single genes encode the catalytic (C) subunit (
kin-1), the regulatory (R) subunit (
kin-2) and an A-kinase anchor protein (AKAP) (
aka-1); nonetheless, PK-A is able to facilitate a comprehensive array of cAMP-mediated processes in this model multicellular organism. We have previously demonstrated that, in C. elegans, as many as 12 different isoforms of the C-subunit arise as a consequence of alternative splicing strategies. Here, we report the occurrence of transcripts encoding novel isoforms of the PK-A R-subunit in C. elegans. In place of exons 1 and 2, these transcripts include coding sequences from novel B or Q exons directly linked to exon 3, thereby generating isoforms with novel N-termini. R-subunits containing an exon B-encoded N-terminal polypeptide sequence were detected in extracts prepared from mixed populations of C. elegans. Of note is the observation that R-subunit isoforms containing exon B- or exon Q-encoded polypeptide sequences lack the dimerisation/docking domains conventionally seen in R-subunits. This means that they are unlikely to participate in the formation of tetrameric PK-A holoenzymes and, additionally, they are unlikely to interact with AKAP(s). It is therefore possible that, in C. elegans, in addition to tetrameric (R(2)C(2)) PK-A holoenzymes, there is also a sub-population of dimeric (RC) PK-A enzymes that are not tethered by AKAPs. Furthermore, inspection of the N-terminal sequence encoded by exon B suggests that this isoform is a likely target for N-myristoylation. Although unusual, a number of similarly N-myristoylatable R-subunits, from a range of different species, are present in the databases, suggesting that this may be a more generally observed feature of R-subunit structure. The occurrence of R-subunit isoforms, without dimerisation/docking domains (with or without N-myristoylatable N-termini) in other species would suggest that the control of PK-A activity may be more complex than hitherto thought.