Analysis of meiosis regulators in human gonads: a sexually dimorphic spatio-temporal expression pattern suggests involvement of DMRT1 in meiotic entry

Abstract

The mitosis-meiosis switch is a key event in the differentiation of germ cells. In humans, meiosis is initiated in fetal ovaries, whereas in testes meiotic entry is inhibited until puberty. The purpose of this study was to examine the expression pattern of meiosis regulators in human gonads and to investigate a possible role of DMRT1 in the regulation of meiotic entry. The expression pattern of DMRT1, STRA8, SCP3, DMC1, NANOS3, CYP26B1 and NANOS2 was investigated by RT-PCR and immunohistochemistry in a series of human testis samples from fetal life to adulthood, and in fetal ovaries. DMRT1 was expressed in testes throughout development but with marked spatio-temporal changes. At the early fetal period of 8-20 gestational weeks (GW) and at infantile mini-puberty, DMRT1 was predominantly expressed in Sertoli cells, whereas at later stages of gestation (22-40 GW), during childhood and in post-pubertal testes, DMRT1 was most abundant in spermatogonia, except in the A-dark type. In fetal ovaries, DMRT1 was detected in oogonia and oocytes until 20 GW, but was completely down-regulated following meiotic entry. STRA8, SCP3 and DMC1 were expressed mainly in oocytes and spermatogonia in accordance with their role in initiation and progression of meiosis. The putative meiosis inhibitors, CYP26B1 and NANOS2, were primarily expressed in Leydig cells and spermatocytes, respectively. In conclusion, the expression pattern of the investigated meiotic regulators is largely conserved in the human gonads compared with rodents, but with some minor differences, such as a stable expression of CYP26B1 in human fetal ovaries. The sexually dimorphic expression pattern of DMRT1 indicates a similar role in the mitosis-meiosis switch in human gonads as previously demonstrated in mice. The biological importance of the changes in expression of DMRT1 in Sertoli cells remains to be established, but it is consistent with DMRT1 reinforcing the inhibition of meiosis in the testis.

Regulation of meiotic entry and gonadal sex differentiation in the human: normal and disrupted signaling

“…The expression of STRA8 is followed by upregulation of SCP3, SPO11, and DMC1, which are markers of meiotic progression. In accordance with this general notion, expression of SCP3 was detected in ovaries from 44) and DMC1 from GW 13 (5,42). In addition, SPO11 and SCP1 expression was detected from GW 13 in human fetal ovaries (5,44).…”

“…In human fetal ovaries, meiotic entry is initiated asynchronously from around GW 10-11 and constitutes the transition from oogonia to oocytes (17,20,22,41). This was recently confirmed by the presence of γH2AX-positive (marks double-strand breaks) oogonia at GW 10 (5) and SCP3-positive oogonia from GW 12-14 (42,43). The pre-meiosis marker STRA8 was expressed before and around this developmental time point (5,6,37,44), with low transcript levels of STRA8 detectable from GW 8-9 (6,44).…”

“…The expression of STRA8 in fetal ovaries peaks around GW 12-14 but remains until GW 18-20 (5,6,44). In contrast to fetal ovaries, STRA8 expression was not detected in human fetal testes (6,42,44). The expression of STRA8 is followed by upregulation of SCP3, SPO11, and DMC1, which are markers of meiotic progression.…”

“…An interesting difference is that in mice, RA is produced in the mesonephros and diffuses to the gonads (45), whereas several recent studies indicate that the human gonads also possess an intrinsic capacity to synthesize RA, based on the expression pattern of the RA-synthesizing enzyme ALDH1A (5,6,42). ALDH1A1 was expressed at similar levels in fetal testes and ovaries and in samples with and without mesonephros (5,6,42). Based on increased expression of ALDH1A coinciding with the initiation of meiosis, Le Bouffant et al (5) suggested that ALDH1A1 might play a role in the initiation of meiosis in fetal ovaries.…”

Mammalian gonocyte and spermatogonia differentiation: recent advances and remaining challenges

“…By contrast, in human and marmoset, a survey of available data on gene expression profiles, cell behaviors (e.g. proliferation or migration), and cell positioning within seminiferous cords (central vs basal location) clearly shows large overlaps of gonocyte and spermatogonial subpopulations for a period spreading from late gestation to early infancy (Sharpe et al 2003, Franke et al 2004, Gaskell et al 2004, Pauls et al 2006, Jørgensen et al 2012, Ewen et al 2013, McKinnell et al 2013, O'Shaughnessy & Fowler 2014.…”