PUBLICATION
The RNA-binding protein Celf1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development
- Authors
- Siddam, A.D., Gautier-Courteille, C., Perez-Campos, L., Anand, D., Kakrana, A., Dang, C.A., Legagneux, V., Méreau, A., Viet, J., Gross, J.M., Paillard, L., Lachke, S.A.
- ID
- ZDB-PUB-180323-1
- Date
- 2018
- Source
- PLoS Genetics 14: e1007278 (Journal)
- Registered Authors
- Gross, Jeffrey
- Keywords
- none
- MeSH Terms
-
- Animals
- CELF1 Protein/physiology*
- Cell Line
- Cell Nucleus/metabolism*
- Cyclin-Dependent Kinase Inhibitor p27/genetics*
- Endodeoxyribonucleases/genetics*
- Gene Expression Regulation
- Lens, Crystalline/cytology
- Lens, Crystalline/growth & development*
- Lens, Crystalline/metabolism
- Mice
- RNA-Binding Proteins/physiology*
- Xenopus Proteins/physiology*
- Xenopus laevis
- Zebrafish
- Zebrafish Proteins/physiology*
- PubMed
- 29565969 Full text @ PLoS Genet.
Citation
Siddam, A.D., Gautier-Courteille, C., Perez-Campos, L., Anand, D., Kakrana, A., Dang, C.A., Legagneux, V., Méreau, A., Viet, J., Gross, J.M., Paillard, L., Lachke, S.A. (2018) The RNA-binding protein Celf1 post-transcriptionally regulates p27Kip1 and Dnase2b to control fiber cell nuclear degradation in lens development. PLoS Genetics. 14:e1007278.
Abstract
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 5' 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping