title: Prokineticin Ligands and Receptors Are Expressed in the Human Fetal Ovary and Regulate Germ Cell Expression of COX2.
abstract: BACKGROUND
  Fetal ovarian development and primordial follicle formation underpin future female fertility. Prokineticin (PROK) ligands regulate cell survival, proliferation, and angiogenesis in adult reproductive tissues including the ovary. However, their expression and function during fetal ovarian development remains unclear.
  
  
  OBJECTIVE
  This study aimed to investigate expression and localization of the PROK ligands, receptors, and their downstream transcriptional targets in the human fetal ovary.
  
  
  METHODS
  This study was conducted at the University of Edinburgh.
  
  
  METHODS
  Ovaries were collected from 37 morphologically normal human fetuses.
  
  
  METHODS
  mRNA and protein expression of PROK ligands and receptors was determined in human fetal ovaries using qRT-PCR, immunoblotting, and immunohistochemistry. Functional studies were performed using a human germ cell tumor line (TCam-2) stably transfected with Prokineticin receptor 1 (PROKR1).
  
  
  RESULTS
  Expression of PROK1 and PROKR1 was significantly higher in mid-gestation ovaries (17-20 wk) than at earlier gestations (8-11 and 14-16 wk). PROK2 significantly increased across the gestations examined. PROKR2 expression remained unchanged. PROK ligand and receptor proteins were predominantly localized to germ cells (including oocytes within primordial follicles) and endothelial cells, indicating these cell types to be the targets of PROK signaling in the human fetal ovary. PROK1 treatment of a germ cell line stably expressing PROKR1 resulted in ERK phosphorylation and elevated COX2 expression.
  
  
  CONCLUSIONS
  Developmental changes in expression and regulation of COX2 and phosphorylated ERK (pERK) by PROK1 suggest that PROK ligands may be novel regulators of germ cell development in the human fetal ovary, interacting within a network of growth and survival factors prior to primordial follicle formation.
authors.affiliation: MRC Centre for Reproductive Health (S.L.E., A.J.C., H.L.K., P.B., H.N.J., R.A.A.) and Biomolecular Core, Shared University Research Facilities (P.B.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK, EH16 4TJ; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK, BT9 7AE (S.L.E.); Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK, NW10TU (A.J.C.).
authors.forename: Sharon L
authors.initials: SL
authors.lastname: Eddie
authors.affiliation: MRC Centre for Reproductive Health (S.L.E., A.J.C., H.L.K., P.B., H.N.J., R.A.A.) and Biomolecular Core, Shared University Research Facilities (P.B.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK, EH16 4TJ; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK, BT9 7AE (S.L.E.); Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK, NW10TU (A.J.C.).
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Childs
authors.affiliation: MRC Centre for Reproductive Health (S.L.E., A.J.C., H.L.K., P.B., H.N.J., R.A.A.) and Biomolecular Core, Shared University Research Facilities (P.B.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK, EH16 4TJ; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK, BT9 7AE (S.L.E.); Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK, NW10TU (A.J.C.).
authors.forename: Hazel L
authors.initials: HL
authors.lastname: Kinnell
authors.affiliation: MRC Centre for Reproductive Health (S.L.E., A.J.C., H.L.K., P.B., H.N.J., R.A.A.) and Biomolecular Core, Shared University Research Facilities (P.B.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK, EH16 4TJ; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK, BT9 7AE (S.L.E.); Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK, NW10TU (A.J.C.).
authors.forename: Pamela
authors.initials: P
authors.lastname: Brown
authors.affiliation: MRC Centre for Reproductive Health (S.L.E., A.J.C., H.L.K., P.B., H.N.J., R.A.A.) and Biomolecular Core, Shared University Research Facilities (P.B.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK, EH16 4TJ; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK, BT9 7AE (S.L.E.); Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK, NW10TU (A.J.C.).
authors.forename: Henry N
authors.initials: HN
authors.lastname: Jabbour
authors.affiliation: MRC Centre for Reproductive Health (S.L.E., A.J.C., H.L.K., P.B., H.N.J., R.A.A.) and Biomolecular Core, Shared University Research Facilities (P.B.), The Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK, EH16 4TJ; Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, UK, BT9 7AE (S.L.E.); Department of Comparative Biomedical Sciences, Royal Veterinary College, London, UK, NW10TU (A.J.C.).
authors.forename: Richard A
authors.initials: RA
authors.lastname: Anderson
mesh_terms: D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D047109:Fetal Development; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005854:Germ Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism*; D010053:Ovary / Q000196:embryology / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D018000:Receptors, Peptide / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; C467610:PROK1 protein, human; C423608:PROK2 protein, human; C470837:PROKR1 protein, human; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; D042662:Vascular Endothelial Growth Factor, Endocrine-Gland-Derived; D051546:Cyclooxygenase 2