Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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ERK1/2 in Ovarian Granulosa Cells are Essential for Female Fertility

ABSTRACT: A surge of luteinizing hormone (LH) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Since the signaling molecules RAS and ERK1/2 are activated by a LH surge in granulosa cells of preovulatory follicles, we disrupted Erk1/2 in mouse granulosa cells and provide in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene in granulosa cells demonstrate that C/EBP is a critical downstream mediator of ERK1/2 activation. These mouse models provide in vivo systems in which to define the context specific and molecular mechanisms by which granulosa cells respond to LH and these mechanisms are relevant to the regulation of human fertility and infertility. Immature wild type or ERK1/2 conditonal knock-out mice were injected with 5IU equine chorionic gonadotropin (eCG)-48h followed by 5 IU hCG injection. The ovarian granulosa cells were collected at hCG 0h, 2.5h, or 4h and the gene expression pforiles were compared by microarray method.

ORGANISM(S): Mus musculus

SUBMITTER: Zhilin Liu

PROVIDER: E-GEOD-15315 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility.

Fan Heng-Yu HY Liu Zhilin Z Shimada Masayuki M Sterneck Esta E Johnson Peter F PF Hedrick Stephen M SM Richards Joanne S JS

Science (New York, N.Y.) 20090501 5929

A surge of luteinizing hormone (LH) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS and ERK1/2 (extracellular signal-regulated kinases 1 and 2) are activated by an LH surge in granulosa cells of preovulatory follicles, we disrupted Erk1/2 in mouse granulosa cells and provide in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and lute ...[more]

PMID: 19443782

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Project description:Luteinizing hormone (LH) activation of the EGF receptor/RAS/ERK1/2 pathway is essential for ovulation and luteinization because granulosa cell depletion of Erk1/2 (Erk1/2gc-/- mice) renders mice completely infertile. Because of their potential as mediators of ERK1/2-dependent granulosa cell differentiation, we disrupted genes encoding the CCAAT/enhancer-binding proteins, (C/EBP) a and C/EBPb. Female Cebpbgc-/- mutant mice but not Cebpagc-/- mice were subfertile whereas Cebpa/bgc-/- double mutant females were sterile. Follicles failed to ovulate, ovaries were devoid of corpora lutea, luteal cell marker genes (Lhcgr, Prlr, Ptgfr, Cyp11a1 and Star) were absent and serum progesterone levels were low. Microarray analyses identified numerous C/EBPa/b target genes in eCG-hCG treated mice. At 4h post-hCG, a subset (19%) of genes altered in the Cebpa/b depleted cells was also altered in Erk1/2 depleted cells; hence they are common effectors of ERK1/2. Additional genes down-regulated in the Cebpa/b depleted cells at 8 and 24h post-hCG include known (Akr1b7, Runx2, Star, Saa3) and novel (Abcb1b, Apln, Igfbp4, Prlr, Ptgfr Timp4) C/EBP target genes including effectors of vascular cell development. Bhmt, a gene controlling methionine metabolism and expressed exclusively in liver and kidney, was high in WT luteal cells but totally absent in Cebpa/b mutant cells. Because numerous genes potentially associated with vascular development were suppressed in the mutant cells, C/EBPa/b appear to dictate the luteinization process by also controlling genes that regulate the formation of the extensive vascular network required to sustain luteal cells. Thus, C/EBPa/b mediate several aspects of granulosa cell differentiation as well as the complex process of luteinization. Five granulosa cell treatments were included: CEBPM-NM-1/M-NM-2 conditional KO ovary, eCG-treated 48h, hCG 4h wild type ovary, eCG-treated 48h, hCG 8h CEBPM-NM-1/M-NM-2 conditional KO ovary, eCG-treated 48h, hCG 8h wild type ovary, eCG-treated 48h, hCG 24h CEBPM-NM-1/M-NM-2 conditional KO ovary, eCG-treated 48h, hCG 24h

Project description:Gonadotropin surge acts on the preovulatory follicle of the ovary to induce luteinization of follicular cells, oocyte meiotic maturation, cumulus expansion and follicular rupture leading to ovulation. These processes are brought about by spatial and temporal changes in transcriptional regulation of genes in the follicular cells in response to the gonadotropin surge. Analysis of gene expression changes in the periovulatory follicular cells will help in delineating the signal transduction pathways involved in the above mentioned processes. In monoovulatory species like bovines, the time interval of 24-28 hours between gonadotropin surge and ovulation provides distinct advantage for studying the temporal changes in the gene expression pattern. Thus, in the present study, we attempt to identify the temporal changes in the global gene expression profile in the periovulatory follicle of buffalo cows in response to gonadotropin surge and the results suggest the involvement of Insulin-like Growth Factor 1 and cytokine signaling pathways in the periovulatory events. Experiment Overall Design: To study the periovulatory gene expression changes in buffalo cows, an induced-ovulation model system involving sequential treatment with PGF2alpha and GnRH was standardized. The follicular wave containing at least one large follicle of ~7mm size was determined by ultrasonography on day 7 of the estrous cycle before administering exogenous PGF2alpha to induce luteolysis and follicular growth. Exogenous GnRH (100Âµg i.m) was administered 36h post PGF2alpha to induce LH surge. The time course of increase in LH levels post GnRH injection was monitored. Since peak LH levels are attained 2 h post GnRH administration, the time intervals of 3 h post GnRH (corresponding to1 h post LH surge) and 24 h post GnRH (corresponding to 22 h post LH surge) were chosen to identify the gene expression profile associated with immediate early and delayed changes in periovulatory follicle respectively. Thus ovaries were collected before, 1 h and 22 h post LH surge and follicle wall and granulosa cells were isolated from the ovaries and snap frozen for the purpose of RNA isolation.

Dataset Information

ERK1/2 in Ovarian Granulosa Cells are Essential for Female Fertility

Publications

MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility.

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