title: Zinc maintains prophase I arrest in mouse oocytes through regulation of the MOS-MAPK pathway.
abstract: Meiosis in mammalian females is marked by two arrest points, at prophase I and metaphase II, which must be tightly regulated in order to produce a haploid gamete at the time of fertilization. The transition metal zinc has emerged as a necessary and dynamic regulator of the establishment, maintenance, and exit from metaphase II arrest, but the roles of zinc during prophase I arrest are largely unknown. In this study, we investigate the mechanisms of zinc regulation during the first meiotic arrest. Disrupting zinc availability in the prophase I arrested oocyte by treatment with the heavy metal chelator N,N,N',N'-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) causes meiotic resumption even in the presence of pharmacological inhibitors of meiosis. We further show that the MOS-MAPK pathway mediates zinc-dependent prophase I arrest, as the pathway prematurely activates during TPEN-induced meiotic resumption. Conversely, inhibition of the MOS-MAPK pathway maintains prophase I arrest. While prolonged zinc insufficiency ultimately results in telophase I arrest, early and transient exposure of oocytes to TPEN is sufficient to induce meiotic resumption and bypass the telophase I block, allowing the formation of developmentally competent eggs upon parthenogenetic activation. These results establish zinc as a crucial regulator of meiosis throughout the entirety of oocyte maturation, including the maintenance of and release from the first and second meiotic arrest points.
authors.affiliation: Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
authors.forename: Betty Y
authors.initials: BY
authors.lastname: Kong
authors.forename: Miranda L
authors.initials: ML
authors.lastname: Bernhardt
authors.forename: Alison M
authors.initials: AM
authors.lastname: Kim
authors.forename: Thomas V
authors.initials: TV
authors.lastname: O'Halloran
authors.forename: Teresa K
authors.initials: TK
authors.lastname: Woodruff
mesh_terms: D000818:Animals; D059447:Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology; D002614:Chelating Agents / Q000494:pharmacology; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D049469:Meiotic Prophase I / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D009865:Oocytes / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D009866:Oogenesis / Q000187:drug effects / Q000502:physiology; D010312:Parthenogenesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D017231:Proto-Oncogene Proteins c-mos / Q000378:metabolism; D013692:Telophase / Q000187:drug effects / Q000502:physiology; D015032:Zinc / Q000172:deficiency / Q000378:metabolism*
chemical_list: D002614:Chelating Agents; D005029:Ethylenediamines; D011500:Protein Synthesis Inhibitors; D017231:Proto-Oncogene Proteins c-mos; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine