The objective of this research proposal is to understand the role of zinc in the control of oocyte maturation. Zinc is one of the most widely utilized metals in biological systems and is an essential co-factor in hundreds of transcription factors, phosphatases, kinases, and metalloenzymes. Management of zinc homeostasis is tightly regulated and over twenty zinc-specific transporters are conserved across mammalian genomes. Three of these zinc-transporting proteins are highly enriched in the mouse oocyte and fertilized egg relative to more than 60 other tissues. Our preliminary findings suggest that three physiological processes may depend on zinc as a specific regulatory factor. Using zinc-specific fluorophores, we have identified the granulosa cells as a source of free zinc and predict that zinc is transported to the oocyte through zinc transport proteins present in the transzonal projections connecting these two cells during follicle development. Secondly, removal of zinc during in vitro maturation of oocytes blocks expansion of the surrounding cumulus cells and causes symmetric cytokinesis of the oocyte rather than asymmetric polar body extrusion. These phenotypes are rescued by exogenous zinc. Finally, delivery of zinc to meiotically mature eggs results in parthenogenic activation. These studies suggest a previously unrecognized link between zinc-dependent signaling pathways and oocyte maturation and are the focus of this application. Our overall hypothesis is that the completion of oocyte maturation in the follicle and transition to a meiotically competent egg depends on zinc regulation and oocyte-enriched zinc-specific receptors. This hypothesis is addressed in three interiinked experimental aims by a highly interdisciplinary team that bridges reproductive science, chemical biology and biophysics. While the phenomenological evidence underlying the proposal strongly supports a regulatory role for zinc in oocyte function, biochemical mechanisms are just beginning to emerge in the literature and from our own preliminary data. The results of studies proposed by this project will provide an innovative new model for oocyte development, and add new member(s) to the family of inorganic signaling molecules (such as Ca2+, NO, 02, and C02) that control fundamental cellular and developmental processes.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Program Projects (P01)
Project #
5P01HD021921-25
Application #
8519487
Study Section
Special Emphasis Panel (ZHD1-DSR-L)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
25
Fiscal Year
2013
Total Cost
$308,404
Indirect Cost
$85,402
Name
Northwestern University at Chicago
Department
Type
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Makanji, Yogeshwar; Zhu, Jie; Mishra, Rama et al. (2014) Inhibin at 90: from discovery to clinical application, a historical review. Endocr Rev 35:747-94
Vanorny, Dallas A; Prasasya, Rexxi D; Chalpe, Abha J et al. (2014) Notch signaling regulates ovarian follicle formation and coordinates follicular growth. Mol Endocrinol 28:499-511
Kong, B Y; Duncan, F E; Que, E L et al. (2014) Maternally-derived zinc transporters ZIP6 and ZIP10 drive the mammalian oocyte-to-egg transition. Mol Hum Reprod 20:1077-89
Hong, Young Pyo; Gleber, Sophie-Charlotte; O'Halloran, Thomas V et al. (2014) Alignment of low-dose X-ray fluorescence tomographyĆ½Ć½images using differential phase contrast. J Synchrotron Radiat 21:229-34
Kim, S-Y; Cordeiro, M H; Serna, V A et al. (2013) Rescue of platinum-damaged oocytes from programmed cell death through inactivation of the p53 family signaling network. Cell Death Differ 20:987-97
Wu, J S; Kim, A M; Bleher, R et al. (2013) Imaging and elemental mapping of biological specimens with a dual-EDS dedicated scanning transmission electron microscope. Ultramicroscopy 128:24-31
Bernhardt, Miranda L; Kong, Betty Y; Kim, Alison M et al. (2012) A zinc-dependent mechanism regulates meiotic progression in mammalian oocytes. Biol Reprod 86:114
Kong, Betty Y; Bernhardt, Miranda L; Kim, Alison M et al. (2012) Zinc maintains prophase I arrest in mouse oocytes through regulation of the MOS-MAPK pathway. Biol Reprod 87:11, 1-12
Jadhav, Unmesh; Jameson, J Larry (2011) Steroidogenic factor-1 (SF-1)-driven differentiation of murine embryonic stem (ES) cells into a gonadal lineage. Endocrinology 152:2870-82
Kim, Alison M; Bernhardt, Miranda L; Kong, Betty Y et al. (2011) Zinc sparks are triggered by fertilization and facilitate cell cycle resumption in mammalian eggs. ACS Chem Biol 6:716-23

Showing the most recent 10 out of 197 publications