Cargando…

The RNA-binding protein Celf1 post-transcriptionally regulates p27(Kip1) and Dnase2b to control fiber cell nuclear degradation in lens development

Opacification of the ocular lens, termed cataract, is a common cause of blindness. To become transparent, lens fiber cells undergo degradation of their organelles, including their nuclei, presenting a fundamental question: does signaling/transcription sufficiently explain differentiation of cells pr...

Descripción completa

Detalles Bibliográficos
Autores principales: Siddam, Archana D., Gautier-Courteille, Carole, Perez-Campos, Linette, Anand, Deepti, Kakrana, Atul, Dang, Christine A., Legagneux, Vincent, Méreau, Agnès, Viet, Justine, Gross, Jeffrey M., Paillard, Luc, Lachke, Salil A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889275/
https://www.ncbi.nlm.nih.gov/pubmed/29565969
http://dx.doi.org/10.1371/journal.pgen.1007278
_version_ 1783312675927752704
author Siddam, Archana D.
Gautier-Courteille, Carole
Perez-Campos, Linette
Anand, Deepti
Kakrana, Atul
Dang, Christine A.
Legagneux, Vincent
Méreau, Agnès
Viet, Justine
Gross, Jeffrey M.
Paillard, Luc
Lachke, Salil A.
author_facet Siddam, Archana D.
Gautier-Courteille, Carole
Perez-Campos, Linette
Anand, Deepti
Kakrana, Atul
Dang, Christine A.
Legagneux, Vincent
Méreau, Agnès
Viet, Justine
Gross, Jeffrey M.
Paillard, Luc
Lachke, Salil A.
author_sort Siddam, Archana D.
collection PubMed
description Opacification of the ocular lens, termed cataract, is a common cause of blindness. To become transparent, lens fiber cells undergo degradation of their organelles, including their nuclei, presenting a fundamental question: does signaling/transcription sufficiently explain differentiation of cells progressing toward compromised transcriptional potential? We report that a conserved RNA-binding protein Celf1 post-transcriptionally controls key genes to regulate lens fiber cell differentiation. Celf1-targeted knockout mice and celf1-knockdown zebrafish and Xenopus morphants have severe eye defects/cataract. Celf1 spatiotemporally down-regulates the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) by interacting with its 5’ UTR and mediating translation inhibition. Celf1 deficiency causes ectopic up-regulation of p21(Cip1). Further, Celf1 directly binds to the mRNA of the nuclease Dnase2b to maintain its high levels. Together these events are necessary for Cdk1-mediated lamin A/C phosphorylation to initiate nuclear envelope breakdown and DNA degradation in fiber cells. Moreover, Celf1 controls alternative splicing of the membrane-organization factor beta-spectrin and regulates F-actin-crosslinking factor Actn2 mRNA levels, thereby controlling fiber cell morphology. Thus, we illustrate new Celf1-regulated molecular mechanisms in lens development, suggesting that post-transcriptional regulatory RNA-binding proteins have evolved conserved functions to control vertebrate oculogenesis.
format Online
Article
Text
id pubmed-5889275
institution National Center for Biotechnology Information
language English
publishDate 2018
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-58892752018-04-20 The RNA-binding protein Celf1 post-transcriptionally regulates p27(Kip1) and Dnase2b to control fiber cell nuclear degradation in lens development Siddam, Archana D. Gautier-Courteille, Carole Perez-Campos, Linette Anand, Deepti Kakrana, Atul Dang, Christine A. Legagneux, Vincent Méreau, Agnès Viet, Justine Gross, Jeffrey M. Paillard, Luc Lachke, Salil A. PLoS Genet Research Article Opacification of the ocular lens, termed cataract, is a common cause of blindness. To become transparent, lens fiber cells undergo degradation of their organelles, including their nuclei, presenting a fundamental question: does signaling/transcription sufficiently explain differentiation of cells progressing toward compromised transcriptional potential? We report that a conserved RNA-binding protein Celf1 post-transcriptionally controls key genes to regulate lens fiber cell differentiation. Celf1-targeted knockout mice and celf1-knockdown zebrafish and Xenopus morphants have severe eye defects/cataract. Celf1 spatiotemporally down-regulates the cyclin-dependent kinase (Cdk) inhibitor p27(Kip1) by interacting with its 5’ UTR and mediating translation inhibition. Celf1 deficiency causes ectopic up-regulation of p21(Cip1). Further, Celf1 directly binds to the mRNA of the nuclease Dnase2b to maintain its high levels. Together these events are necessary for Cdk1-mediated lamin A/C phosphorylation to initiate nuclear envelope breakdown and DNA degradation in fiber cells. Moreover, Celf1 controls alternative splicing of the membrane-organization factor beta-spectrin and regulates F-actin-crosslinking factor Actn2 mRNA levels, thereby controlling fiber cell morphology. Thus, we illustrate new Celf1-regulated molecular mechanisms in lens development, suggesting that post-transcriptional regulatory RNA-binding proteins have evolved conserved functions to control vertebrate oculogenesis. Public Library of Science 2018-03-22 /pmc/articles/PMC5889275/ /pubmed/29565969 http://dx.doi.org/10.1371/journal.pgen.1007278 Text en © 2018 Siddam et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Siddam, Archana D.
Gautier-Courteille, Carole
Perez-Campos, Linette
Anand, Deepti
Kakrana, Atul
Dang, Christine A.
Legagneux, Vincent
Méreau, Agnès
Viet, Justine
Gross, Jeffrey M.
Paillard, Luc
Lachke, Salil A.
The RNA-binding protein Celf1 post-transcriptionally regulates p27(Kip1) and Dnase2b to control fiber cell nuclear degradation in lens development
title The RNA-binding protein Celf1 post-transcriptionally regulates p27(Kip1) and Dnase2b to control fiber cell nuclear degradation in lens development
title_full The RNA-binding protein Celf1 post-transcriptionally regulates p27(Kip1) and Dnase2b to control fiber cell nuclear degradation in lens development
title_fullStr The RNA-binding protein Celf1 post-transcriptionally regulates p27(Kip1) and Dnase2b to control fiber cell nuclear degradation in lens development
title_full_unstemmed The RNA-binding protein Celf1 post-transcriptionally regulates p27(Kip1) and Dnase2b to control fiber cell nuclear degradation in lens development
title_short The RNA-binding protein Celf1 post-transcriptionally regulates p27(Kip1) and Dnase2b to control fiber cell nuclear degradation in lens development
title_sort rna-binding protein celf1 post-transcriptionally regulates p27(kip1) and dnase2b to control fiber cell nuclear degradation in lens development
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889275/
https://www.ncbi.nlm.nih.gov/pubmed/29565969
http://dx.doi.org/10.1371/journal.pgen.1007278
work_keys_str_mv AT siddamarchanad thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT gautiercourteillecarole thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT perezcamposlinette thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT ananddeepti thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT kakranaatul thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT dangchristinea thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT legagneuxvincent thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT mereauagnes thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT vietjustine thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT grossjeffreym thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT paillardluc thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT lachkesalila thernabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT siddamarchanad rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT gautiercourteillecarole rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT perezcamposlinette rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT ananddeepti rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT kakranaatul rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT dangchristinea rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT legagneuxvincent rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT mereauagnes rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT vietjustine rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT grossjeffreym rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT paillardluc rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment
AT lachkesalila rnabindingproteincelf1posttranscriptionallyregulatesp27kip1anddnase2btocontrolfibercellnucleardegradationinlensdevelopment