%0 Journal Article
%T The RNA-binding protein Celf1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development
%A Agn¨¨s M¨Śreau
%A Archana D. Siddam
%A Atul Kakrana
%A Carole Gautier-Courteille
%A Christine A. Dang
%A Deepti Anand
%A Jeffrey M. Gross
%A Justine Viet
%A Linette Perez-Campos
%A Luc Paillard
%A Salil A. Lachke
%A Vincent Legagneux
%J -
%D 2018
%R 10.1371/journal.pgen.1007278
%X 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 p27Kip1 by interacting with its 5ĄŻ UTR and mediating translation inhibition. Celf1 deficiency causes ectopic up-regulation of p21Cip1. 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
%K Lens (anatomy)
%K Optical lenses
%K Zebrafish
%K Mouse models
%K Cell differentiation
%K Cataracts
%K Eyes
%K Messenger RNA
%U https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1007278