New strains for tissue-specific RNAi studies in <i>Caenorhabditis elegans</i>

Watts, Jennifer L.; Harrison, Henry F.; Omi, Shizue; Dalelio, James; Guenther, Quentin; Pujol, Nathalie

doi:10.1101/283325

Cited by 8 publications

(11 citation statements)

References 45 publications

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“…nas-38 is expressed prominently in the epidermis and there promotes AMP expression through STA-2 [36]. To confirm this directly, we knocked down nas-38(ok3407) with RNAi specifically in the epidermis [53]. This suppressed the increased nlp-29 expression phenotype to a similar extent as sta-2, supporting the idea that nas-38 acts in skin tissue (Figures 3I, S4H).…”

Section: Nas-38 Is Required In the Epidermis To Increase Amp Expressionsupporting

confidence: 54%

Innate Immunity Promotes Sleep through Epidermal Antimicrobial Peptides

et al. 2021

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Wounding and infection trigger a protective innate immune response that includes the production of antimicrobial peptides in the affected tissue as well as increased sleep. Little is known, however, how peripheral wounds or innate immunity signal to the nervous system to increase sleep. We found that during C. elegans larval molting, an epidermal tolloid/BMP-1-like protein called NAS-38 promotes sleep. NAS-38 is negatively regulated by its thrombospondin domain and acts through its astacin protease domain to activate p38 MAP/PMK-1 kinase and TGF-β-SMAD/SMA-3-dependent innate immune pathways in the epidermis that cause STAT/STA-2 and SLC6 (solute carrier)/SNF-12-dependent expression of antimicrobial peptide (AMP) genes. We show that more than a dozen epidermal AMPs act as somnogens, signaling across tissues to promote sleep through the sleep-active RIS neuron. In the adult, epidermal injury activates innate immunity and turns up AMP production to trigger sleep, a process that overlaps with EGFR signaling that is known to promote sleep following cellular stress. We show for one AMP, NLP-29, that it acts through the neuropeptide receptor NPR-12 in locomotion-controlling neurons that are presynaptic to RIS and that depolarize this neuron to induce sleep. Sleep in turn increases the chance of surviving injury. Thus, we found a novel mechanism by which peripheral wounds signal to the nervous system to increase protective sleep. Such a cross-tissue somnogen signaling function of AMPs might also boost sleep in other animals including humans.

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Section: Nas-38 Is Required In the Epidermis To Increase Amp Expressionsupporting

confidence: 54%

Innate Immunity Promotes Sleep through Epidermal Antimicrobial Peptides

et al. 2021

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“…In contrast, pals-5 induction was less compromised by zip-1(RNAi) in the epidermal-specific RNAi strain. Because intestinal expression of rde-1 allows generation of secondary siRNAs that can spread to other tissues and silence gene expression there, we used a separate tissue-specific RNAi strain, where the sid-1 transport channel is specifically expressed in the intestine (27, 28). These mutants do not suffer from the problem of leakiness seen in the rde-1 rescue strains (28, 29).…”

Section: Resultsmentioning

confidence: 99%

“…Because intestinal expression of rde-1 allows generation of secondary siRNAs that can spread to other tissues and silence gene expression there, we used a separate tissue-specific RNAi strain, where the sid-1 transport channel is specifically expressed in the intestine (27, 28). These mutants do not suffer from the problem of leakiness seen in the rde-1 rescue strains (28, 29). However, we did note that they suffer from the opposite problem: they appear to be somewhat resistant to RNAi.…”

Section: Resultsmentioning

confidence: 99%

The predicted bZIP transcription factor ZIP-1 promotes resistance to intracellular infection in Caenorhabditis elegans

Lazetic

et al. 2021

Preprint

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Defense against intracellular infection has been extensively studied in vertebrate hosts, but less is known about invertebrate hosts. For example, almost nothing is known about the transcription factors that induce defense against intracellular infection in the model nematode Caenorhabditis elegans. Two types of intracellular pathogens that naturally infect C. elegans are the Orsay virus, which is a positive-sense RNA virus, and microsporidia, which are fungal pathogens. Surprisingly, these molecularly distinct pathogens induce a common host transcriptional response called the Intracellular Pathogen Response (IPR). Here we describe zip-1 as an IPR regulator that functions downstream of all known IPR activating and regulatory pathways. zip-1 encodes a putative bZIP transcription factor of previously unknown function, and we show how zip-1 controls induction of a subset of genes upon IPR activation. ZIP-1 protein is expressed in the nuclei of intestinal cells, and is required in the intestine to upregulate IPR gene expression. Importantly, zip-1 promotes resistance to infection by the Orsay virus and by microsporidia in intestinal cells. Altogether, our results indicate that zip-1 represents a central hub for all triggers of the IPR, and that this transcription factor plays a protective role against intracellular pathogen infection in C. elegans.

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“…In flies, lifespan was extended by manipulation of mTORC1 pathway components using GAL4-UAS drivers primarily expressed in the fat body 8 . However, further research has shown that both tissue-specific RNAi 24 and GAL4-UAS drivers have off-target effects in other tissues 25 . In addition to being more tissue-specific than RNAi, AID has the added benefit of targeting the endogenous protein directly rather than silencing a gene at the mRNA level.…”

Section: Discussionmentioning

confidence: 99%

Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction inC. elegans

Smith

Lanjuin

Sharma

et al. 2021

Preprint

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One of the most robust and reproducible methods to prolong lifespan in a variety of organisms is inhibition of the mTORC1 (mechanistic target of rapamycin complex 1) pathway. mTORC1 is a metabolic sensor that promotes anabolic growth when nutrients are abundant. Inhibition of mTORC1 extends lifespan, but also frequently has other effects such as stunted growth, slowed development, reduced fertility, and disrupted metabolism. It has long been assumed that suppression of anabolism and resulting phenotypes such as impaired growth and reproduction may be causal to mTORC1 longevity, but this hypothesis has not been directly tested. RAGA-1 is an upstream activator of TORC1. Previous work from our lab using a C. elegans model of mTORC1 longevity, the long-lived raga-1 null mutant, found that the presence of RAGA-1 only in the neurons suppresses longevity of the null mutant. Here, we use the auxin-inducible degradation (AID) system to test whether neuronal mTORC1 inhibition is sufficient for longevity, and whether any changes in lifespan are also linked to stunted growth or fertility. We find that life-long AID of RAGA-1 either in all somatic tissue or only in the neurons of C. elegans is sufficient to extend lifespan. We also find that AID of RAGA-1 or LET-363/mTOR beginning at day 1 of adulthood extends lifespan to a similar extent. Unlike somatic degradation of RAGA-1, neuronal degradation of RAGA-1 does not impair growth, slow development, or decrease the reproductive capacity of the worms. Lastly, while AID of LET-363/mTOR in all somatic cells shortens lifespan, neuronal AID of LET-363/mTOR promotes longevity. This work demonstrates that targeting mTORC1 specifically in the neurons uncouples longevity from growth and reproductive impairments, challenging previously held ideas about the mechanisms of mTORC1 longevity and elucidating the promise of tissue-specific aging therapeutics.

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New strains for tissue-specific RNAi studies in Caenorhabditis elegans

Cited by 8 publications

References 45 publications

Innate Immunity Promotes Sleep through Epidermal Antimicrobial Peptides

Innate Immunity Promotes Sleep through Epidermal Antimicrobial Peptides

The predicted bZIP transcription factor ZIP-1 promotes resistance to intracellular infection in Caenorhabditis elegans

Neuronal mTORC1 inhibition promotes longevity without suppressing anabolic growth and reproduction inC. elegans

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