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An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans

In the nematode C. elegans, insulin signaling regulates development and aging in response to the secretion of numerous insulin peptides. Here, we describe a novel, non-signaling isoform of the nematode insulin receptor (IR), DAF-2B, that modulates insulin signaling by sequestration of insulin peptid...

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Autores principales: Martinez, Bryan A, Reis Rodrigues, Pedro, Nuñez Medina, Ricardo M, Mondal, Prosenjit, Harrison, Neale J, Lone, Museer A, Webster, Amanda, Gurkar, Aditi U, Grill, Brock, Gill, Matthew S
Formato: Online Artículo Texto
Lenguaje:English
Publicado: eLife Sciences Publications, Ltd 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041946/
https://www.ncbi.nlm.nih.gov/pubmed/32096469
http://dx.doi.org/10.7554/eLife.49917
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author Martinez, Bryan A
Reis Rodrigues, Pedro
Nuñez Medina, Ricardo M
Mondal, Prosenjit
Harrison, Neale J
Lone, Museer A
Webster, Amanda
Gurkar, Aditi U
Grill, Brock
Gill, Matthew S
author_facet Martinez, Bryan A
Reis Rodrigues, Pedro
Nuñez Medina, Ricardo M
Mondal, Prosenjit
Harrison, Neale J
Lone, Museer A
Webster, Amanda
Gurkar, Aditi U
Grill, Brock
Gill, Matthew S
author_sort Martinez, Bryan A
collection PubMed
description In the nematode C. elegans, insulin signaling regulates development and aging in response to the secretion of numerous insulin peptides. Here, we describe a novel, non-signaling isoform of the nematode insulin receptor (IR), DAF-2B, that modulates insulin signaling by sequestration of insulin peptides. DAF-2B arises via alternative splicing and retains the extracellular ligand binding domain but lacks the intracellular signaling domain. A daf-2b splicing reporter revealed active regulation of this transcript through development, particularly in the dauer larva, a diapause stage associated with longevity. CRISPR knock-in of mScarlet into the daf-2b genomic locus confirmed that DAF-2B is expressed in vivo and is likely secreted. Genetic studies indicate that DAF-2B influences dauer entry, dauer recovery and adult lifespan by altering insulin sensitivity according to the prevailing insulin milieu. Thus, in C. elegans alternative splicing at the daf-2 locus generates a truncated IR that fine-tunes insulin signaling in response to the environment.
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spelling pubmed-70419462020-02-27 An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans Martinez, Bryan A Reis Rodrigues, Pedro Nuñez Medina, Ricardo M Mondal, Prosenjit Harrison, Neale J Lone, Museer A Webster, Amanda Gurkar, Aditi U Grill, Brock Gill, Matthew S eLife Developmental Biology In the nematode C. elegans, insulin signaling regulates development and aging in response to the secretion of numerous insulin peptides. Here, we describe a novel, non-signaling isoform of the nematode insulin receptor (IR), DAF-2B, that modulates insulin signaling by sequestration of insulin peptides. DAF-2B arises via alternative splicing and retains the extracellular ligand binding domain but lacks the intracellular signaling domain. A daf-2b splicing reporter revealed active regulation of this transcript through development, particularly in the dauer larva, a diapause stage associated with longevity. CRISPR knock-in of mScarlet into the daf-2b genomic locus confirmed that DAF-2B is expressed in vivo and is likely secreted. Genetic studies indicate that DAF-2B influences dauer entry, dauer recovery and adult lifespan by altering insulin sensitivity according to the prevailing insulin milieu. Thus, in C. elegans alternative splicing at the daf-2 locus generates a truncated IR that fine-tunes insulin signaling in response to the environment. eLife Sciences Publications, Ltd 2020-02-25 /pmc/articles/PMC7041946/ /pubmed/32096469 http://dx.doi.org/10.7554/eLife.49917 Text en © 2020, Martinez et al http://creativecommons.org/licenses/by/4.0/ http://creativecommons.org/licenses/by/4.0/This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited.
spellingShingle Developmental Biology
Martinez, Bryan A
Reis Rodrigues, Pedro
Nuñez Medina, Ricardo M
Mondal, Prosenjit
Harrison, Neale J
Lone, Museer A
Webster, Amanda
Gurkar, Aditi U
Grill, Brock
Gill, Matthew S
An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans
title An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans
title_full An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans
title_fullStr An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans
title_full_unstemmed An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans
title_short An alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in C. elegans
title_sort alternatively spliced, non-signaling insulin receptor modulates insulin sensitivity via insulin peptide sequestration in c. elegans
topic Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7041946/
https://www.ncbi.nlm.nih.gov/pubmed/32096469
http://dx.doi.org/10.7554/eLife.49917
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