Abstract
During human fetal ovary development, the process of primordial follicle formation is immediately preceded by a highly dynamic period of germ cell and somatic cell reorganisation. This is regulated by germ-cell specific transcription regulators, by the conserved RNA binding proteins DAZL and BOLL and by secreted growth factors of the TGFβ family, including activin βA: these all show changing patterns of expression preceding follicle formation. In mice, the transcription factor Nobox is essential for follicle formation and oocyte survival, and NOBOX regulates the expression of GDF9 in humans. We have therefore characterised the expression of GDF9 in relation to these known key factors during follicle formation in the human fetal ovary. mRNA levels of GDF9, BMP15 and NOBOX were quantified by qRT-PCR and showed dramatic increases across gestation. GDF9 protein expression was localised by immunohistochemistry to the same population of germ cells as those expressing activin βA prior to follicle formation but did not co-localise with either BOLL or DAZL. A novel NOBOX isoform was identified in fetal ovary that was shown to be capable of up-regulating the GDF9 promoter in reporter assays. Thus, during oogenesis in humans, oocytes go through a dynamic and very sharply demarcated sequence of changes in expression of these various proteins, even within individual germ cell nests, likely to be of major functional significance in determining selective germ cell survival at this key stage in ovarian development. Transcriptional variation may contribute to the range of age of onset of POI in women with NOBOX mutations.
Highlights
The timely breakdown of oocyte nests into individual primordial follicles in the immature ovary is critical to female fertility, and occurs in fetal life in the human
The onset of meiosis [6,7] follows germ cell nest formation and germ cells switch from expressing the RNA binding protein DAZL, which is required for entry into meiosis [8], reviewed in [9], to expressing the related protein BOLL as cells go through zygotene and pachytene [10]
Our data indicate that human germ cells transiently express both activin βA and Growth and differentiation factor 9 (GDF9), with the latter likely to be under NOBOX control, in the lead-up to primordial follicle formation
Summary
The timely breakdown of oocyte nests into individual primordial follicles in the immature ovary is critical to female fertility, and occurs in fetal life in the human. BMP15 ( known as GDF9B), is co-expressed with GDF9 in oocytes and shows species differences in its function: loss of BMP15 in sheep leads to sterility [21] while in mice its loss has a mild effect on fertility [22] It appears that while TGFβ family growth factors including activin and potentially GDF9, are key factors regulating germ cell development, oocyte specific transcription factors such as NOBOX act as master regulators of these and other key oocyte genes [23,24]. We have investigated here whether GDF9 and BMP15 are expressed in the human fetal ovary at the time of oocyte nest breakdown and primordial follicle formation and whether GDF9 expression at this time might be regulated by NOBOX. Our data indicate that human germ cells transiently express both activin βA and GDF9, with the latter likely to be under NOBOX control, in the lead-up to primordial follicle formation
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