Dicer1 Ablation in the Mouse Epididymis Causes Dedifferentiation of the Epithelium and Imbalance in Sex Steroid Signaling

Abstract

BackgroundThe postnatal development of the epididymis is a complex process that results in a highly differentiated epithelium, divided into several segments. Recent studies indicate a role for RNA interference (RNAi) in the development of the epididymis, however, the actual requirement for RNAi has remained elusive. Here, we present the first evidence of a direct need for RNAi in the differentiation of the epididymal epithelium.Methodology/Principal FindingsBy utilizing the Cre-LoxP system we have generated a conditional knock-out of Dicer1 in the two most proximal segments of the mouse epididymis. Recombination of Dicer1, catalyzed by Defb41iCre/wt, took place before puberty, starting from 12 days postpartum. Shortly thereafter, downregulation of the expression of two genes specific for the most proximal epididymis (lipocalin 8 and cystatin 8) was observed. Following this, segment development continued until week 5 at which age the epithelium started to regress back to an undifferentiated state. The dedifferentiated epithelium also showed an increase in estrogen receptor 1 expression while the expression of androgen receptor and its target genes; glutathione peroxidase 5, lipocalin 5 and cysteine-rich secretory protein 1 was downregulated, indicating imbalanced sex steroid signaling.Conclusions/SignificanceAt the time of the final epididymal development, Dicer1 acts as a regulator of signaling pathways essential for maintaining epithelial cell differentiation.

Epididymal small non‐coding RNA studies: progress over the past decade

“…The ablation of Dicer1 caused the dedifferentiation of the epithelium, the imbalance in sex steroid signaling (Bjorkgren et al, 2012) and lipid homeostasis (Bjorkgren et al, 2015), and the down-regulation of b-defensin genes and the consequential decline in antibacterial ability (Tang et al, 2018). Because of the lethal effect of Dicer1 full knockout, two conditional Dicer1 knockout mouse models were developed to remove the miRNAs in the caput epididymal regions.…”

“…Because of the lethal effect of Dicer1 full knockout, two conditional Dicer1 knockout mouse models were developed to remove the miRNAs in the caput epididymal regions. The ablation of Dicer1 caused the dedifferentiation of the epithelium, the imbalance in sex steroid signaling (Bjorkgren et al, 2012) and lipid homeostasis (Bjorkgren et al, 2015), and the down-regulation of b-defensin genes and the consequential decline in antibacterial ability (Tang et al, 2018). Although some of these effects are postulated to be miRNA-independent, or as an indirect function mediated by the androgen receptor shown to closely interact with some miRNAs , these lines of evidence still implicate the involvement of miRNAs in controlling the epididymal development, as well as the response to different stress conditions.…”

A mouse model with tamoxifen‐inducible thyrocyte‐specific cre recombinase activity

“…The serum T4 levels were measured using the commercial ELISA (Trinity Biotech, NY, USA) according to manufacturer's instructions. Quantitative PCR for Dicer1 was performed as described earlier (Bj€ orkgren et al, 2012). Procedures of animal care and use in this study were approved by the Regierungspr€ asidium Karlsruhe (Karlsruhe, Germany).…”

The epididymis and its role on sperm quality and male fertility

“…In the last decade, small non-coding RNAs such as microRNAs (miRNAs) have gained attention as critical regulators of gene expression in several biological processes, including differentiation of the epididymal epithelium and acquisition of male fertility (Bjorkgren et al, 2012;Hawkins et al, 2011;Papaioannou and Nef, 2010). Consisting of about 22 nucleotides, miRNAs regulate posttranscriptional gene expression by targeting mRNAs for cleavage or translational repression (Bartel, 2009).…”