Enhanced neuronal RNAi in C. elegans using SID-1

Calixto, Andrea; Chelur, Dattananda S.; Topalidou, Irini; Chen, Xiaoyin; Chalfie, Martin

doi:10.1038/nmeth.1463

Cited by 352 publications

(394 citation statements)

References 34 publications

(51 reference statements)

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“…Ingested dsRNA can cross the intestine into the fluid-filled body cavity that surrounds all tissues, including the germline, without SID-1-dependent entry into the cytosol of intestinal cells (33)(34)(35). To determine where subsequent entry into the cytosol in parents is required for silencing in progeny, we delivered dsRNA into the extracellular space by injecting into the body cavity beyond the bend of the posterior gonad arm (Fig.…”

Section: Forms Of Dsrna Reach Progeny and Spread Between Cells In Thementioning

confidence: 99%

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

Marre

Traver

Jose

2016

Proc. Natl. Acad. Sci. U.S.A.

104

144

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Experiences during the lifetime of an animal have been proposed to have consequences for subsequent generations. Although it is unclear how such intergenerational transfer of information occurs, RNAs found extracellularly in animals are candidate molecules that can transfer gene-specific regulatory information from one generation to the next because they can enter cells and regulate gene expression. In support of this idea, when double-stranded RNA (dsRNA) is introduced into some animals, the dsRNA can silence genes of matching sequence and the silencing can persist in progeny. Such persistent gene silencing is thought to result from sequencespecific interaction of the RNA within parents to generate chromatin modifications, DNA methylation, and/or secondary RNAs, which are then inherited by progeny. Here, we show that dsRNA can be directly transferred between generations in the worm Caenorhabditis elegans. Intergenerational transfer of dsRNA occurs even in animals that lack any DNA of matching sequence, and dsRNA that reaches progeny can spread between cells to cause gene silencing. Surprisingly, extracellular dsRNA can also reach progeny without entry into the cytosol, presumably within intracellular vesicles. Fluorescently labeled dsRNA is imported from extracellular space into oocytes along with yolk and accumulates in punctate structures within embryos. Subsequent entry into the cytosol of early embryos causes gene silencing in progeny. These results demonstrate the transport of extracellular RNA from one generation to the next to regulate gene expression in an animal and thus suggest a mechanism for the transmission of experience-dependent effects between generations.circulating RNA | parental RNAi | epigenetics | transgenerational inheritance | endocytosis

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Section: Forms Of Dsrna Reach Progeny and Spread Between Cells In Thementioning

confidence: 99%

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

Marre

Traver

Jose

2016

Proc. Natl. Acad. Sci. U.S.A.

104

144

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“…However, both forms of dsRNA delivery could result in the direct entry of dsRNA into the germline without entry into the cytoplasm of somatic cells. Ingested dsRNA is transcytosed across the gut into the body cavity that surrounds the germline (20,21), and it is difficult to avoid spillage of injected dsRNA into the body cavity. These experimental considerations suggest that to test the possibility of somatic tissues initiating transgenerational gene silencing, it is necessary to express silencing triggers within somatic tissues and examine gene silencing within the germline.…”

Section: Significancementioning

confidence: 99%

“…Such transgenerational silencing can be triggered by both injected dsRNA (14)(15)(16) and ingested dsRNA (16)(17)(18)(19). However, both injection and ingestion can deliver dsRNA directly into the fluid-filled body cavity that surrounds the germline, without entry into the cytosol of any somatic cell (20,21). Thus, it remains unknown whether somatic cells in C. elegans can export signals for delivery into the germline to cause transgenerational gene silencing.…”

mentioning

confidence: 99%

Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing

Devanapally

Ravikumar

Jose

2015

Proc. Natl. Acad. Sci. U.S.A.

124

132

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An animal that can transfer gene-regulatory information from somatic cells to germ cells may be able to communicate changes in the soma from one generation to the next. In the worm Caenorhabditis elegans, expression of double-stranded RNA (dsRNA) in neurons can result in the export of dsRNA-derived mobile RNAs to other distant cells. Here, we show that neuronal mobile RNAs can cause transgenerational silencing of a gene of matching sequence in germ cells. Consistent with neuronal mobile RNAs being forms of dsRNA, silencing of target genes that are expressed either in somatic cells or in the germline requires the dsRNA-selective importer SID-1. In contrast to silencing in somatic cells, which requires dsRNA expression in each generation, silencing in the germline is heritable after a single generation of exposure to neuronal mobile RNAs. Although initiation of inherited silencing within the germline requires SID-1, a primary Argonaute RDE-1, a secondary Argonaute HRDE-1, and an RNase D homolog MUT-7, maintenance of inherited silencing is independent of SID-1 and RDE-1, but requires HRDE-1 and MUT-7. Inherited silencing can persist for >25 generations in the absence of the ancestral source of neuronal dsRNA. Therefore, our results suggest that sequence-specific regulatory information in the form of dsRNA can be transferred from neurons to the germline to cause transgenerational silencing.epigenetics | mobile RNAs | soma to germline | Weismann barrier

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“…sid-1 encodes a novel membrane protein, SID-1, that is widely expressed in non-neuronal cells, especially those exposed to the environment, and localizes to the cell periphery (2). Although C. elegans neuronal cells are normally resistant to systemic RNAi, ectopic expression of SID-1 in these cells sensitize them to systemic RNAi (3). Genetic evidence suggests that SID-1 functions cell-autonomously and is involved in import rather than export of interfering RNAs between cells (2,4), but the precise molecular function and biochemical activity of SID-1 in RNA transport remains unresolved.…”

Section: Sid-1 Acts Cell-autonomously and Is Required For Cellular Immentioning

confidence: 99%

Systemic RNA Interference Deficiency-1 (SID-1) Extracellular Domain Selectively Binds Long Double-stranded RNA and Is Required for RNA Transport by SID-1

Koutmou

Leahy

et al. 2015

Journal of Biological Chemistry

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Enhanced neuronal RNAi in C. elegans using SID-1

Cited by 352 publications

References 34 publications

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

Extracellular RNA is transported from one generation to the next in Caenorhabditis elegans

Double-stranded RNA made in C. elegans neurons can enter the germline and cause transgenerational gene silencing

Systemic RNA Interference Deficiency-1 (SID-1) Extracellular Domain Selectively Binds Long Double-stranded RNA and Is Required for RNA Transport by SID-1

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