title: GDF9 is transiently expressed in oocytes before follicle formation in the human fetal ovary and is regulated by a novel NOBOX transcript.
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.
authors: MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors: Rosemary A L
authors: RA
authors: Bayne
authors: MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors: Hazel L
authors: HL
authors: Kinnell
authors: MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors: Shiona M
authors: SM
authors: Coutts
authors: MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors: Jing
authors: J
authors: He
authors: Department of Comparative Biomedical Sciences, The Royal Veterinary College, London, United Kingdom.
authors: Andrew J
authors: AJ
authors: Childs
authors: MRC Centre for Reproductive Health, University of Edinburgh, Queen's Medical Research Institute, Edinburgh, United Kingdom.
authors: Richard A
authors: RA
authors: Anderson
mesh_terms: D028341:Activins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D055430:Bone Morphogenetic Protein 15 / Q000235:genetics / Q000378:metabolism; D005260:Female; D005333:Fetus / Q000378:metabolism; D005854:Germ Cells / Q000378:metabolism; D055429:Growth Differentiation Factor 9 / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism*; D006080:Ovarian Follicle / Q000254:growth & development; D010053:Ovary / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D017434:Protein Structure, Tertiary; D016601:RNA-Binding Proteins / Q000378:metabolism; D016415:Sequence Alignment; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C481351:BOLL protein, human; D055430:Bone Morphogenetic Protein 15; C101358:DAZL protein, human; C525897:GDF9 protein, human; D055429:Growth Differentiation Factor 9; D018398:Homeodomain Proteins; C506600:NOBOX protein, human; D020033:Protein Isoforms; D016601:RNA-Binding Proteins; D014157:Transcription Factors; C422405:activin A; D028341:Activins