Dicer is required for Sertoli cell function and survival

Abstract

Dicer is a key enzyme that processes microRNA precursors into their mature form, enabling them to regulate gene expression. Dicer null mutants die before gastrulation. To study Dicer function in testis development, we crossed mice carrying a conditional Dicer allele with an AMH-Cre transgenic line, thereby inactivating Dicer in Sertoli cells around embryonic day 14.0 (E14.0). Dicer null Sertoli cells show normal embryonic development, and at postnatal day 0 (P0), testis tubules are normal in number and histologically undistinguishable from controls. Subsequently, Dicer-mutant testes show a progressively aberrant development, so that at P6, they contain a reduced number of disorganized testis tubules leading to primary sterility. Apoptosis and prophase I assays reveal a massive wave of apoptosis starting at P3, causing progressive loss of Sertoli cells, but also of germ cells, resulting in drastically reduced testis size. Expression of genes that play crucial roles in testis development, structural integrity and spermatogenesis is downregulated at P0, before morphological changes become apparent, indicating that Dicer-mutant testes are already transcriptionally compromised at this stage. Taken together, the results of this study show that Dicer is required for Sertoli cell function and survival and for spermatogenesis in mice.

Gonadotrope-specific Deletion of Dicer Results in Severely Suppressed Gonadotropins and Fertility Defects

“…In the male germ line, miRNAs are important for the proliferation of primordial germ cells and spermatogonia but are dispensable for the repression of retrotransposons in developing germ cells (62,63). Deletion of Dicer in Sertoli cells causes proliferation and maturation defects and eventually results in failure of germ cell maintenance (62,64,65). All of the above genetic models have illustrated the important roles of DICER-mediated miRNAs in various reproductive tissues.…”

UPF2, a nonsense-mediated mRNA decay factor, is required for prepubertal Sertoli cell development and male fertility by ensuring fidelity of the transcriptome

“…The dual-fluorescent reporter (Rosa26mTmG) line allows for easy and convenient determination of the onset of Cre activity when crossed with a specific Cre deletor line (Wu et al, 2012). Using this method, we detected Cre activity in Amh-Cre males at ∼E12.5, which is ∼2 days earlier than in an alternative Amh-Cre line (∼E14.5) (Gao et al, 2006;Kim et al, 2010). At E12.5, SC specification has completed and the testis cord has just become morphologically distinguishable.…”

“…and small RNA biogenetic factors (e.g. Dicer1) (Sharpe et al, 2003;Nalam et al, 2009;Kim et al, 2010;Matson et al, 2011;Kato et al, 2012). It appears that proper cell fate control during prepubertal SC development involves the precise temporal activation of transcriptional cascades in response to hormonal stimulation (e.g.…”

“…Notably, among these dysregulated genes are those encoding core splicing factors (e.g. SR proteins and hnRNPs) and those known to be essential for prepubertal SCs to switch from proliferation to differentiation at ∼P10, such as Wt1, Sox8 and Dicer1 (Gao et al, 2006;Barrionuevo and Scherer, 2010;Kim et al, 2010). Therefore, the NMD pathway, in addition to its canonical function in reducing transcriptional noise, also appears to be involved in the control of expression of a subset of genes crucial for SC development.…”

Cell‐specific ablation in the testis: what have we learned?

“…It has been shown that Sertoli cells will undergo apoptosis postnatally in mice lacking Sertoli cell expression of Dicer, which is required for micro RNA and small interfering RNA biogenesis (Papaioannou et al ., 2009; Kim et al ., 2010). Sertoli cell apoptosis starts at about postnatal day 3 in these animals although some Sertoli cells survive into adulthood.…”