TOR Deficiency in C. elegans Causes Developmental Arrest and Intestinal Atrophy by Inhibition of mRNA Translation

AbstractThe translation initiation complex eIF3 imparts specialized functions to regulate protein expression. However, understanding of eIF3 activities in neurons remains limited despite widespread dysregulation of eIF3 subunits in neurological disorders. Here, we report a selective role of theC. elegansRNA-binding subunit EIF-3.G in shaping the neuronal protein landscape. We identify a missense mutation in the conserved Zinc-Finger (ZF) of EIF-3.G that acts in a gain-of-function manner to dampen neuronal hyperexcitation. Using neuron type-specific seCLIP, we systematically mapped EIF-3.G-mRNA interactions and identified EIF-3.G occupancy on GC-rich 5′UTRs of a select set of mRNAs enriched in activity-dependent functions. We demonstrate that the ZF mutation in EIF-3.G alters translation in a 5′UTR dependent manner. Our study reveals anin vivomechanism for eIF3 in governing neuronal protein levels to control activity states and offers insights into how eIF3 dysregulation contributes to neuronal disorders.

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C. elegans provide milk for their young

10.1101/2020.11.15.380253 ◽

2020 ◽

Author(s):

Carina C. Kern ◽

StJohn Townsend ◽

Antoine Salzmann ◽

Nigel B. Rendell ◽

Graham W. Taylor ◽

...

Keyword(s):

Sexual Maturity ◽

Reproductive Effort ◽

Pacific Salmon ◽

Resource Transfer ◽

C Elegans ◽

Destructive Process ◽

Severe Pathology ◽

Intestinal Atrophy ◽

Insight Into

AbstractAdult C. elegans hermaphrodites exhibit severe senescent pathology that begins to develop within days of reaching sexual maturity (Ezcurra et al., 2018; Garigan et al., 2002; Herndon et al., 2002; Wang et al., 2018). For example, after depletion of self-sperm, intestinal biomass is converted into yolk leading to intestinal atrophy and yolk steatosis (pseudocoelomic lipoprotein pools, PLPs) (Ezcurra et al., 2018; Garigan et al., 2002; Herndon et al., 2002; Sornda et al., 2019). These senescent pathologies are promoted by insulin/IGF-1 signalling (IIS), which also shortens lifespan (Ezcurra et al., 2018; Kenyon, 2010). This pattern of rapid and severe pathology in organs linked to reproduction is reminiscent of semelparous organisms where massive reproductive effort leads to rapid death (reproductive death) as in Pacific salmon (Finch, 1990; Gems et al., 2020). Moreover, destructive conversion of somatic biomass to support reproduction is a hallmark of reproductive death (Gems et al., 2020). Yet arguing against the occurrence of reproductive death in C. elegans is the apparent futility of post-reproductive yolk production. Here we show that this effort is not futile, since post-reproductive mothers vent yolk through their vulva, which is consumed by progeny and supports their growth; thus vented yolk functions as a milk, and C. elegans mothers exhibit a form of lactation. Moreover, IIS promotes lactation, thereby effecting a costly process of resource transfer from postreproductive mothers to offspring. These results support the view that C. elegans hermaphrodites exhibit reproductive death involving a self-destructive process of lactation that is promoted by IIS. They also provide new insight into how the strongly life-shortening effects of IIS in C. elegans evolved.

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Rescue of a developmental arrest caused by a C. elegans heat-shock transcription-factor mutation by loss of ribosomal S6-kinase activity

10.1101/310086 ◽

2018 ◽

Author(s):

Peter Chisnell ◽

T. Richard Parenteau ◽

Elizabeth Tank ◽

Kaveh Ashrafi ◽

Cynthia Kenyon

Keyword(s):

Transcription Factor ◽

Transcription Factors ◽

Heat Shock ◽

Heat Shock Transcription Factor ◽

Adult Longevity ◽

Loss Of Function ◽

S6 Kinase ◽

Heat Shock Transcription Factors ◽

C Elegans ◽

Developmental Arrest

AbstractThe widely conserved heat-shock response, regulated by heat shock transcription factors, is not only essential for cellular stress resistance and adult longevity, but also for proper development. However, the genetic mechanisms by which heat-shock transcription factors regulate development are not well understood. In C. elegans, we conducted an unbiased genetic screen to identify mutations that could ameliorate the developmental arrest phenotype of a heat-shock factor mutant. Here we show that loss of the conserved translational activator rsks-1/S6-Kinase, a downstream effector of TOR kinase, can rescue the developmental-arrest phenotype of hsf-1 partial loss-of-function mutants. Unexpectedly, we show that the rescue is not likely caused by reduced translation, nor to activation of any of a variety of stress-protective genes and pathways. Our findings identify an as-yet unexplained regulatory relationship between the heat-shock transcription factor and the TOR pathway during C. elegans’ development.

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Eukaryotic initiation factor EIF-3.G augments mRNA translation efficiency to regulate neuronal activity

eLife ◽

10.7554/elife.68336 ◽

2021 ◽

Vol 10 ◽

Author(s):

Stephen M Blazie ◽

Seika Takayanagi-Kiya ◽

Katherine M McCulloch ◽

Yishi Jin

Keyword(s):

Neuronal Activity ◽

Rna Binding ◽

Mrna Translation ◽

Initiation Factor ◽

Translation Efficiency ◽

Dependent Manner ◽

C Elegans ◽

Protein Levels ◽

Neuronal Protein

The translation initiation complex eIF3 imparts specialized functions to regulate protein expression. However, understanding of eIF3 activities in neurons remains limited despite widespread dysregulation of eIF3 subunits in neurological disorders. Here, we report a selective role of the C. elegans RNA-binding subunit EIF-3.G in shaping the neuronal protein landscape. We identify a missense mutation in the conserved Zinc-Finger (ZF) of EIF-3.G that acts in a gain-of-function manner to dampen neuronal hyperexcitation. Using neuron type-specific seCLIP, we systematically mapped EIF-3.G-mRNA interactions and identified EIF-3.G occupancy on GC-rich 5′UTRs of a select set of mRNAs enriched in activity-dependent functions. We demonstrate that the ZF mutation in EIF-3.G alters translation in a 5′UTR dependent manner. Our study reveals an in vivo mechanism for eIF3 in governing neuronal protein levels to control neuronal activity states and offers insights into how eIF3 dysregulation contributes to neuronal disorders.

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A Single-copy Knock In Translating Ribosome ImmunoPrecipitation (SKI TRIP) tool kit for tissue specific profiling of actively translated mRNAs in C. elegans.

10.1101/2021.12.22.473890 ◽

2021 ◽

Author(s):

Laura E Wester ◽

Anne Lanjuin ◽

Emanuel H W Bruckisch ◽

Maria C Perez Matos ◽

Caroline Heintz ◽

...

Keyword(s):

Affinity Purification ◽

Ribosomal Subunit ◽

Mrna Translation ◽

Single Copy ◽

Specific Cell ◽

Cell Type ◽

Specific Expression ◽

Tissue Specific ◽

C Elegans ◽

Cell Type Specific

Translating Ribosome Affinity Purification (TRAP) methods have emerged as a powerful approach to profile actively translated transcripts in specific cell and tissue types. Epitope tagged ribosomal subunits are expressed in defined cell populations and used to pull down ribosomes and their associated mRNAs, providing a snapshot of cell type-specific translation occurring in that space and time. Current TRAP toolkits available to the C. elegans community have been built using multi-copy arrays, randomly integrated in the genome. Here we introduce a Single-copy Knock In Translating Ribosome ImmunoPrecipitation (SKI TRIP) tool kit, a collection of C. elegans strains engineered by CRISPR in which tissue specific expression of FLAG tagged ribosomal subunit protein RPL-22 is driven by cassettes present in single copy from defined sites in the genome. In depth characterization of the SKI TRIP strains and methodology shows that 3xFLAG tagged RPL-22 expressed from its endogenous locus or within defined cell types incorporates into actively translating ribosomes and can be used to efficiently and cleanly pull-down cell type specific transcripts without impacting overall mRNA translation or fitness of the animal. We propose SKI TRIP use for the study of processes that are acutely sensitive to changes in translation, such as aging.

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Nutritional control of mRNA isoform expression during developmental arrest and recovery in C. elegans

Genome Research ◽

10.1101/gr.133587.111 ◽

2012 ◽

Vol 22 (10) ◽

pp. 1920-1929 ◽

Cited By ~ 34

Author(s):

C. S. Maxwell ◽

I. Antoshechkin ◽

N. Kurhanewicz ◽

J. A. Belsky ◽

L. R. Baugh

Keyword(s):

C Elegans ◽

Developmental Arrest ◽

Isoform Expression ◽

Mrna Isoform

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Evidence for a Temporal Window of Argonaute Surveillance Prior to mRNA Translation in the C. Elegans Germline

SSRN Electronic Journal ◽

10.2139/ssrn.3155858 ◽

2018 ◽

Author(s):

Meetu Seth ◽

Masaki Shirayama ◽

Wen Tang ◽

En-zhi Shen ◽

Shikui Tu ◽

...

Keyword(s):

Mrna Translation ◽

Temporal Window ◽

C Elegans

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Sleep Counteracts Aging Phenotypes to Survive Starvation-Induced Developmental Arrest in C. elegans

Current Biology ◽

10.1016/j.cub.2018.10.009 ◽

2018 ◽

Vol 28 (22) ◽

pp. 3610-3624.e8 ◽

Cited By ~ 20

Author(s):

Yin Wu ◽

Florentin Masurat ◽

Jasmin Preis ◽

Henrik Bringmann

Keyword(s):

C Elegans ◽

Developmental Arrest

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C. elegans hermaphrodites undergo semelparous reproductive death

10.1101/2020.11.16.384255 ◽

2020 ◽

Cited By ~ 1

Author(s):

Carina C. Kern ◽

Shivangi Srivastava ◽

Marina Ezcurra ◽

Nancy Hui ◽

StJohn Townsend ◽

...

Keyword(s):

Caenorhabditis Elegans ◽

Sibling Species ◽

Early Onset ◽

Reproductive Effort ◽

Pacific Salmon ◽

Larval Growth ◽

Present Evidence ◽

C Elegans ◽

Species Pairs ◽

Intestinal Atrophy

AbstractAgeing in the nematode Caenorhabditis elegans is unusual in terms of the severity and early onset of senescent pathology, particularly affecting organs involved in reproduction (Ezcurra et al., 2018; Garigan et al., 2002; Herndon et al., 2002). In post-reproductive C. elegans hermaphrodites, intestinal biomass is converted into yolk leading to intestinal atrophy and yolk steatosis (Ezcurra et al., 2018; Sornda et al., 2019). We recently showed that post-reproductive mothers vent yolk which functions as a milk (yolk milk), supporting larval growth that is consumed by larvae (Kern et al., 2020). This form of massive reproductive effort involving biomass repurposing leading to organ degeneration is characteristic of semelparous organisms (i.e. that exhibit only a single reproductive episode) ranging from monocarpic plants to Pacific salmon where it leads to rapid death (reproductive death) (Finch, 1990; Gems et al., 2020). Removal of the germline greatly increases lifespan in both C. elegans and Pacific salmon, in the latter case by suppressing semelparous reproductive death (Hsin and Kenyon, 1999; Robertson, 1961). Here we present evidence that reproductive death occurs in C. elegans, and that it is suppressed by germline removal, leading to extension of lifespan. Comparing three Caenorhabditis sibling species pairs with hermaphrodites and females, we show that lactation and massive early pathology only occurs in the former. In each case, hermaphrodites are shorter lived and only in hermaphrodites does germline removal markedly increase lifespan. Semelparous reproductive death has previously been viewed as distinct from ageing; however, drawing on recent theories of ageing (Blagosklonny, 2006; de Magalhães and Church, 2005; Maklakov and Chapman, 2019), we argue that it involves exaggerated versions of programmatic mechanisms that to a smaller extent contribute to ageing in non-semelparous species. Thus, despite the presence of reproductive death, mechanisms of ageing in C. elegans are informative about ageing in general.

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