Inactivation of the Celf1 Gene that Encodes an RNA-Binding Protein Delays the First Wave of Spermatogenesis in Mice

Abstract

BackgroundThe first wave of spermatogenesis in mammals is characterized by a sequential and synchronous appearance of germ cells in the prepubertal testis. Post-transcriptional controls of gene expression play important roles in this process but the molecular actors that underlie them are poorly known.Methodology/principal findingsWe evaluated the requirement for the RNA-binding protein CELF1 during the first wave of spermatogenesis in mice. Mice inactivated for Celf1 gene were not viable on pure genetic backgrounds. On a mixed background, we observed by histology and gene profiling by RT-qPCR that the testes of inactivated prepubertal mice were characterized by several features. (i) Spermiogenesis (differentiation of post-meiotic cells) was blocked in a subset of prepubertal inactivated mice. (ii) The appearance of the different stages of germ cell development was delayed by several days. (iii) The expression of markers of Leydig cells functions was similarly delayed.Conclusions/significance Celf1 disruption is responsible for a blockage of spermiogenesis both in adults and in prepubertal males. Hence, the spermiogenesis defects found in Celf1-inactivated adults appear from the first wave of spermiogenesis. The disruption of Celf1 gene is also responsible for a fully penetrant delayed first wave of spermatogenesis, and a delay of steroidogenesis may be the cause for the delay of germ cells differentiation.

CELFish ways to modulate mRNA decay

“…CELF1 is also overexpressed and/or mislocalized in other neuromuscular disorders, supporting the hypothesis that it plays a special role in muscle tissue [95, 104, 131]. Deletion of CELF1 in mice is neonatally lethal in a pure genetic background [132] and results in greatly reduced viability in mixed genetic backgrounds. Those mice that survive have significantly retarded growth, and compromised fertility in both sexes [133].…”

“…This is not surprising because during the process of meiosis, transcription ceases, leaving only post-transcriptional mechanisms to regulate gene expression. As mentioned above, CELF1 −/− mice have reduced fertility, and in males this coincides with spermatogenesis defects [132, 133]. CELF1 and CELF3 (BRUNOL1) are both highly expressed in testes, and CELF3 −/− mice have reduced sperm count and motility but are otherwise normal and fertile [165].…”

Hypogonadism Associated with Cyp19a1 (Aromatase) Posttranscriptional Upregulation in Celf1 Knockout Mice

“…We next investigated a putative causal relationship between defective spermatogenesis (8) and high aromatase activity, resulting in hypogonadism in Celf1 Ϫ/Ϫ . We can raise Celf1 Ϫ/Ϫ mice only on a mixed genetic background because the mutation is homozygous lethal on a pure background (9), resulting in variable expressivity of spermatogenesis defects. As previously observed (8), Celf1 Ϫ/Ϫ testes could be grouped into three classes.…”

“…The Celf1 gene is largely expressed in mouse testis, and mice with a targeted disruption of Celf1 (referred to here as Celf1 Ϫ/Ϫ mice) display an arrest of spermiogenesis just before the round spermatids start elongating (8). This blockage is observed in adults but also during the first wave of spermatogenesis (9). CELF1 is a multifunctional RBP, with a nuclear and cytoplasmic localization (10).…”

The RNA-binding proteins CELF1 and ELAVL1 cooperatively control RNA isoform production

“…Finally, the phenotypes caused in mice by disrupting their genes look much alike. In a pure genetic background, inactivating either Elavl1 or Celf1 causes embryo death (Cibois et al, 2012;Katsanou et al, 2009). Conditional inactivation of Elavl1 (Chi et al, 2011) and constitutive inactivation of Celf1 in a mixed genetic background (Boulanger et al, 2015) showed that both ELAVL1 and CELF1 are required for spermatogenesis.…”