The RNA-binding protein Celf1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development

Archana D Siddam , Carole Gautier-Courteille (1) , Linette Perez-Campos , Deepti Anand , Atul Kakrana , Christine A Dang , Vincent Legagneux (1) , Agnès Méreau (1) , Justine Viet (1) , Jeffrey M Gross , Luc Paillard (1) , Salil A Lachke

1 IGDR - Institut de Génétique et Développement de Rennes

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.

Domaines: Génomique, Transcriptomique et Protéomique [q-bio.GN]

Archana D Siddam, Carole Gautier-Courteille, Linette Perez-Campos, Deepti Anand, Atul Kakrana, et al.. The RNA-binding protein Celf1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development. PLoS Genetics, 2018, 14 (3), pp.e1007278. ⟨10.1371/journal.pgen.1007278⟩. ⟨hal-01773341⟩