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[
Dev Cell,
2022]
In a recent issue of Nature Cell Biology, Ouyang etal. examined the dynamics of double-stranded-RNA-induced gene-silencing across the Caenorhabditis elegans germline and in different subcellular locations. They distinguished among several small RNA amplification loops which complement each other and only together achieve full gene expression inhibition.
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[
Front Biosci,
1997]
The deleted in colorectal cancer (DCC) gene encodes a neural cell adhesion family molecule that was originally identified as a candidate tumor suppressor target of 18q allelic loss in colorectal cancer. However, the importance of the DCC protein has been most clearly demonstrated in neural development. Mutational and subsequent biochemical studies in C. elegans, Drosophila and vertebrates have shown that DCC functions in the guided migration of cells and cell processes in response to stimuli from netrins, a family of secreted laminin-like proteins. It appears that DCC may act in this signal transduction pathway as a netrin receptor or a component of the receptor complex, though a definitive receptor:ligand relationship has not yet been demonstrated. It is also clear that DCC can affect migrations in a netrin-independent manner, implying the existence of other DCC ligands. Though the loss of DCCexpression appears to be a later event in several malignancies and is associated with disease dissemination, it has not been adequately demonstrated that DCC is the tumor suppressor gene targeted by 18q allelic loss. However, DCC expression does have potential clinical utility as it stratifies an important group of colorectal cancer patients into good and poor prognosis subgroups.
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[
Sci Adv,
2023]
In <i>Caenorhabditis elegans</i> worms, epigenetic information transmits transgenerationally. Still, it is unknown whether the effects transfer to the next generation inside or outside of the nucleus. Here, we use the tractability of gene-specific double-stranded RNA-induced silencing to demonstrate that RNA interference can be inherited independently of any nuclear factors via mothers that are genetically engineered to transmit only their ooplasm but not the oocytes' nuclei to the next generation. We characterize the mechanisms and, using RNA sequencing, chimeric worms, and sequence polymorphism between different isolates, identify endogenous small RNAs which, similarly to exogenous siRNAs, are inherited in a nucleus-independent manner. From a historical perspective, these results might be regarded as partial vindication of discredited cytoplasmic inheritance theories from the 19th century, such as Darwin's "pangenesis" theory.
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[
Elife,
2023]
Intermediate filaments (IFs) are major components of the metazoan cytoskeleton. A long-standing debate concerns the question whether IF network organization only reflects or also determines cell and tissue function. Using <i>C. elegans</i>, we have recently described mutants of the MAPK SMA-5 which perturb the organization of the intestinal IF cytoskeleton resulting in luminal widening and cytoplasmic invaginations. Besides these structural phenotypes, systemic dysfunctions were also observed. We now identify the IF polypeptide IFB-2 as a highly efficient suppressor of both the structural and functional deficiencies of <i>
sma-5</i> animals, by removing the aberrant IF network. Mechanistically, perturbed IF network morphogenesis is linked to hyperphosphorylation of multiple sites throughout the entire IFB-2 molecule. The rescuing capability is IF isotype-specific and not restricted to SMA-5 mutants but extends to mutants that disrupt the function of the cytoskeletal linker IFO-1 and the IF-associated protein BBLN1. The findings provide strong evidence for adverse consequences of the deranged IF networks with implications for diseases that are characterized by altered IF network organization.
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[
FEBS Lett,
1995]
The complete cDNA clone for a cytoplasmic intermediate filament (IF) protein from the annelid Lumbricus terrestris reported here, shows an extra 42 residues in the coil 1b subdomain of the central rod, as do the IF proteins from nematodes and molluscs. These extra six heptads are also present in all nuclear lamins but not in any known vertebrate cytoplasmic IF protein. Thus, it seems that protostomic metazoa conserve a lamin-like structural element in their cytoplasmic IF proteins, which was lost in the deuterostomic metazoan branch leading to the vertebrates.
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[
Nature,
2009]
Dietary restriction is the most effective and reproducible intervention to extend lifespan in divergent species. In mammals, two regimens of dietary restriction, intermittent fasting (IF) and chronic caloric restriction, have proven to extend lifespan and reduce the incidence of age-related disorders. An important characteristic of IF is that it can increase lifespan even when there is little or no overall decrease in calorie intake. The molecular mechanisms underlying IF-induced longevity, however, remain largely unknown. Here we establish an IF regimen that effectively extends the lifespan of Caenorhabditis elegans, and show that the low molecular weight GTPase RHEB-1 has a dual role in lifespan regulation; RHEB-1 is required for the IF-induced longevity, whereas inhibition of RHEB-1 mimics the caloric-restriction effects. RHEB-1 exerts its effects in part by the insulin/insulin growth factor (IGF)-like signalling effector DAF-16 in IF. Our analyses demonstrate that most fasting-induced upregulated genes require RHEB-1 function for their induction, and that RHEB-1 and TOR signalling are required for the fasting-induced downregulation of an insulin-like peptide, INS-7. These findings identify the essential role of signalling by RHEB-1 in IF-induced longevity and gene expression changes, and suggest a molecular link between the IF-induced longevity and the insulin/IGF-like signalling pathway.
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Richardson CA, Jarosinska OD, Akhmanova A, Remmelzwaal S, Kroll JR, Leube RE, Boxem M, van der Horst S, Pasolli M, Geisler F, Ramalho JJ, Altelaar M, Stucchi R
[
Curr Biol,
2021]
Epithelial tubes are essential components of metazoan organ systems that control the flow of fluids and the exchange of materials between body compartments and the outside environment. The size and shape of the central lumen confer important characteristics to tubular organs and need to be carefully controlled. Here, we identify the small coiled-coil protein BBLN-1 as a regulator of lumen morphology in the C. elegans intestine. Loss of BBLN-1 causes the formation of bubble-shaped invaginations of the apical membrane into the cytoplasm of intestinal cells and abnormal aggregation of the subapical intermediate filament (IF) network. BBLN-1 interacts with IF proteins and localizes to the IF network in an IF-dependent manner. The appearance of invaginations is a result of the abnormal IF aggregation, indicating a direct role for the IF network in maintaining lumen homeostasis. Finally, we identify bublin (BBLN) as the mammalian ortholog of BBLN-1. When expressed in the C. elegans intestine, BBLN recapitulates the localization pattern of BBLN-1 and can compensate for the loss of BBLN-1 in early larvae. In mouse intestinal organoids, BBLN localizes subapically, together with the IF protein keratin 8. Our results therefore may have implications for understanding the role of IFs in regulating epithelial tube morphology in mammals.
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[
J Mech Behav Biomed Mater,
2016]
Intermediate filament (IF) proteins are known mainly by their propensity to form viscoelastic filamentous networks within cells. In addition, IF-proteins are essential parts of various biological materials, such as horn and hagfish slime threads, which exhibit a range of mechanical properties from hard to elastic. These properties and their self-assembly nature made IF-proteins attractive building blocks for biomimetic and biological materials in diverse applications. Here we show that a type V IF-protein, the Caenorhabditis elegans nuclear lamin (Ce-lamin), is a promising building block for protein-based fibers. Electron cryo-tomography of vitrified sections enabled us to depict the higher ordered assembly of the Ce-lamin into macroscopic fibers through the creation of paracrystalline fibers, which are prominent in vitro structures of lamins. The lamin fibers respond to tensile force as other IF-protein-based fibers, i.e., hagfish slime threads, and possess unique mechanical properties that may potentially be used in certain applications. The self-assembly nature of lamin proteins into a filamentous structure, which is further assembled into a complex network, can be easily modulated. This knowledge may lead to a better understanding of the relationship in IF-proteins-based fibers and materials, between their hierarchical structures and their mechanical properties.
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[
Gene,
2019]
Intermediate filaments (IF) belong to major cytoskeletal components of metazoan cells. We have previously determined a tissue specific expression and assembly properties of all eleven cytoplasmic IFs (IFA-1 - IFA-4, IFB-1, IFB-2, IFC-1, IFC-2, IFD-1, IFD-2, IFP-1) in C. elegans and reported an essential function for four (IFA-1, IFA-2, IFA-3 and IFB-1) of them. In this study we continued the characterisation of the IF proteins in C. elegans by searching for in vivo polymerisation partners of the IFA proteins. Using the murine IFA-1 to IFA-3-specific monoclonal Ab MH4 and the immunoprecipitation assay as a tool, we identified the heteropolymeric IFA-1/IFB-1 complexes in the whole nematode protein extract, confirming their existence also in vivo. Moreover, in the present study we also analysed evolutionary aspects of the IF proteins in C. elegans and in nematodes. We found 106 C. elegans IF homologs in different nematode clades. Phylogenetic analyses suggest that all nematode IFs (including the three newly identified IF sequences IFA-5, IFCDP-1 and IFCDP-2) might arose from a AB-type IF ancestor through repeated gene duplications and sequence divergence. Interestingly, the C. elegans IF proteins IFA-1 and IFB-1 represent a heteropolymeric IF cytoskeleton in all investigated nematodes, in contrast to other sequences restricted to the clade III-V (IFA-2, IFA-4), III (IFA-5) and V (IFB-2, IFCDP) taxa, or even to the Caenorhabditis genus (IFA-3, IFC-1 to IFP-1). These analyses provide an insight into the origin of the multiple IFs in nematodes and also represent a basis for further studies of these sequences in nematodes.
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[
Cytoskeleton (Hoboken),
2017]
The dimerisation properties of six intestine-expressed intermediate filament (IF) proteins (B2, C1, C2, D1, D2, E1) were analysed in blot overlay assay on membranes containing all of the eleven recombinant C. elegans IF proteins (A1, A2, A3, A4, B1, B2, C1, C2, D1, D2 and E1). The interactions detected in the blot assays exclusively comprise intestine-expressed IF proteins and the protein A4, which is found in the dauer larva intestine. 86% of these interactions are heterotypic, while the remaining interactions relate to C1, C2 and D2 homodimers. These multiple modes of interaction were also supported by calculations of the numbers of possible interchain ionic interactions derived from the individual rod sequences. The results predict that the six B2, C1, C2, D1, D2 and E1 IF proteins are able to form as many as eleven different heteropolymeric and three homopolymeric IFs in the C. elegans intestine. This simple model of the intestinal IF meshwork enables us to speculate that our previously reported triple RNAi worms arrested or decreased their growth because of feeding reduction due to morphological defects of the mechanically-compromised intestine. This article is protected by copyright. All rights reserved.