Opposing effects of retinoic acid and FGF9 onNanos2expression and meiotic entry of mouse germ cells

Abstract

SummaryIn the mouse, three genes that are homologous to the Drosophila Nanos (Nos) gene have been identified. Deletion of one of these genes, Nanos2, results in male sterility, owing to loss of germ cells during fetal life. Before apoptosis, Nanos2-null gonocytes enter meiosis, suggesting that Nanos2 functions as a meiotic repressor. Here, we show that Nanos2 is continuously expressed in male germ cells from fetal gonocytes to postnatal spermatogonial stem cells. We observed that the promeiotic factor AtRA, an analog of retinoic acid (RA), downregulates NANOS2 levels, in both fetal and postnatal gonocytes, while promoting meiosis. Interestingly, FGF9, a growth factor crucial for sex differentiation and survival of fetal gonocytes, upregulates levels of NANOS2 in both male and female primordial germ cells (PGCs) and in premeiotic spermatogonia. This effect was paralleled by an impairment of meiotic entry, suggesting that FGF9 acts as an inhibitor of meiosis through the upregulation of Nanos2. We found that NANOS2 interacts with PUM2, and that these two proteins colocalize in the ribonucleoparticle and polysomal fractions on sucrose gradients, supporting the notion that they bind RNA. Finally, we found that recombinant NANOS2 binds to two spermatogonial mRNAs, Gata2 and Taf7l, which are involved in germ-cell differentiation.

NOTCH signaling in Sertoli cells regulates gonocyte fate

“…53 We found that several transcripts were differentially regulated in a manner consistent with NOTCH signaling activation in Sertoli cells and with premature differentiation of germ cells. For instance, RBPJ target genes such as Hey1 and Heyl were upregulated in Sertoli cells, as expected; in germ cells, Nanos2, a gene that suppresses meiosis, 54 was downregulated, and genes that are expressed at the beginning of or during meiosis, such as Stra8 and Rec8, 55,56 were all upregulated (GSE37073). Furthermore, in accord with the observation that germ cell differentiation had taken place, a significant decrease in Pou5f1 (a marker for undifferentiated spermatogonia) 57 and a significant increase in Sohlh2 (a marker for differentiating spermatogonia) 58 were also found in these mutant germ cells.…”

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

“…By contrast, the addition of RA reduced NANOS2 expression and concomitantly induced KIT and STRA8 expression in these cells (Barrios et al 2010). Moreover, in PND7 mice, PLZF, a transcription factor required for SSC maintenance (Buaas et al 2004), was shown to act as a repressor on the Kit promoter, preventing KIT expression, whereas isolated Thy1 C spermatogonia from Plzf K/K mice showed more than a doubling in their KIT expression (Filipponi et al 2007).…”

“…C , KIT -mouse germ cells express high levels of NANOS2, a RNA-binding protein involved in SSC self-renewal and in the suppression of spermatogonial differentiation (Suzuki & Saga 2008, Suzuki et al 2009, Sada et al 2012, in response to FGF9, a growth factor produced by Sertoli cells (Barrios et al 2010). By contrast, the addition of RA reduced NANOS2 expression and concomitantly induced KIT and STRA8 expression in these cells (Barrios et al 2010).…”

Cycling to and from a stem cell niche: the temporal and spatial odyssey of mitotic male germ cells

“…This action prevents meiosis from occurring in the fetal testis, and assists in the commitment of male germ cells to the spermatogenic pathway. Other factors involved in this commitment of germ cells to the male program include FGF9 and NANOS2 (Barrios et al, 2010, Bowles et al, 2010, Suzuki and Saga, 2008. Beginning at E11.5, male germ cells rely upon FGF9 for survival, and it has been proposed that FGF9 supports NANOS2 production in these cells to prevent meiotic entry and the activation of events downstream of RA (Barrios et al, 2010, Bowles et al, 2010, DiNapoli et al, 2006, Suzuki and Saga, 2008.…”