CUG-BP1/CELF1 is a multifunctional RNA-binding protein involved in the regulation of alternative splicing and translation. To elucidate its role in mammalian development, we produced mice in which the Cugbp1 gene was inactivated by homologous recombination. These Cugbp1 ؊/؊ mice were viable, although a significant portion of them did not survive after the first few days of life. They displayed growth retardation, and most Cugbp1 ؊/؊ males and females exhibited impaired fertility. Male infertility was more thoroughly investigated. Histological examination of testes from Cugbp1 ؊/؊ males showed an arrest of spermatogenesis that occurred at step 7 of spermiogenesis, before spermatid elongation begins, and an increased apoptosis. A quantitative reverse transcriptase PCR analysis showed a decrease of all the germ cell markers tested but not of Sertoli and Leydig markers, suggesting a general decrease in germ cell number. In wild-type testes, CUG-BP1 is expressed in germ cells from spermatogonia to round spermatids and also in Sertoli and Leydig cells. These findings demonstrate that CUG-BP1 is required for completion of spermatogenesis.Following transcription, a eukaryotic pre-mRNA undergoes nuclear maturation. The mature mRNA is then exported to the cytoplasm, where its stability and translation are finely regulated. It is increasingly clear that a strong link exists between the nuclear and the cytoplasmic events that affect a pre-mRNA and the resulting mRNA. This is illustrated by the observation that a number of RNA-binding proteins, such as those belonging to the CELF or BRUNOL family, control both the splicing of pre-mRNA and the cytoplasmic fate of mature mRNA.The vertebrate CELF family consists of six members, and the name (CUG-BP1 and ETR-3 Like Factors) was derived from the two founding members, CUG-BP1/CELF1 and ETR-3/CUG-BP2/CELF2 (19). The same family was also named BRUNOL (Bruno-like) due to the sequence similarity that its members share with Drosophila melanogaster Bruno (15). The biochemical functions of these proteins are numerous. In mammals, CELF1 to CELF6 were shown to regulate the alternative splicing of some pre-mRNA by stimulating either inclusion or skipping of nonconstitutive exons (for a review, see reference 1). Furthermore, in the cytoplasm, by binding to the 5Ј regions of the cognate mRNAs, CUG-BP1/CELF1 stimulates the translation of the cdk inhibitor p21 and determines the translation initiation codon of the transcription factor C/EBP␤ (41, 42). CUG-BP2/CELF2 controls the stability and the translation of cyclooxygenase-2 mRNA by binding to the 3Ј untranslated region (3ЈUTR) (26). In Xenopus embryos, EDEN-BP (embryo deadenylation element-binding protein,

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.