The RNA-binding protein Celf1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development
In: ISSN: 1553-7390, 2018
Online
academicJournal
Zugriff:
International audience ; 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 zeb-rafish 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 phosphory-lation 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.
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The RNA-binding protein Celf1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development
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Autor/in / Beteiligte Person: | Siddam, Archana ; Gautier-Courteille, Carole ; Perez-Campos, Linette ; Anand, Deepti ; Kakrana, Atul ; Dang, Christine ; Legagneux, Vincent ; Méreau, Agnès ; Viet, Justine ; Gross, Jeffrey ; Paillard, Luc ; Lachke, Salil ; Institut de Génétique et Développement de Rennes (IGDR) ; Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ) ; R01EY021505, National Eye Institute (US) ; France, Retina ; Fight for Sight (US) ; Ministerio de Ciencia Tecnología y Telecomunicaciones (CR) |
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Zeitschrift: | ISSN: 1553-7390, 2018 |
Veröffentlichung: | HAL CCSD ; Public Library of Science, 2018 |
Medientyp: | academicJournal |
DOI: | 10.1371/journal.pgen.1007278 |
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