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Control of oocyte release by progesterone receptor-regulated gene expression.

Robker RL, Akison LK, Russell DL - Nucl Recept Signal (2009)

Bottom Line: The cellular mechanisms by which PGR regulates ovulation are currently under investigation, with several downstream pathways having been identified as PGR-regulated and potentially involved in follicular rupture.Interestingly, none of these PGR-regulated genes has been demonstrated to be a direct transcriptional target of PGR.Rather, in ovarian granulosa cells, PGR may act as an inducible coregulator for constitutively bound Sp1/Sp3 transcription factors, which are key regulators for a discrete cohort of ovulatory genes.

View Article: PubMed Central - PubMed

Affiliation: The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, SA, Australia. rebecca.robker@adelaide.edu.au

ABSTRACT
The progesterone receptor (PGR) is a nuclear receptor transcription factor that is essential for female fertility, in part due to its control of oocyte release from the ovary, or ovulation. In all mammals studied to date, ovarian expression of PGR is restricted primarily to granulosa cells of follicles destined to ovulate. Granulosa cell expression of PGR is induced by the pituitary Luteinizing Hormone (LH) surge via mechanisms that are not entirely understood, but which involve activation of Protein Kinase A and modification of Sp1/Sp3 transcription factors on the PGR promoter. Null mutations for PGR or treatment with PGR antagonists block ovulation in all species analyzed, including humans. The cellular mechanisms by which PGR regulates ovulation are currently under investigation, with several downstream pathways having been identified as PGR-regulated and potentially involved in follicular rupture. Interestingly, none of these PGR-regulated genes has been demonstrated to be a direct transcriptional target of PGR. Rather, in ovarian granulosa cells, PGR may act as an inducible coregulator for constitutively bound Sp1/Sp3 transcription factors, which are key regulators for a discrete cohort of ovulatory genes.

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Mice  for PGR (PRKO) demonstrate that PGR is essential for ovulation, particularly follicular rupture, but not follicle growth or luteinization.Upper panels show ovary sections from mice heterozygous or  for PGR that were treated with PMSG to stimulate preovulatory follicle growth.  Lower panels show ovary sections from mice treated with PMSG followed by hCG for 48h to stimulate ovulation and luteinization.  Lower right panel shows that in PRKO mice, oocytes remain trapped within luteinized follicles.  (Reprinted with permission from Robker et al., 2000).
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fig3: Mice for PGR (PRKO) demonstrate that PGR is essential for ovulation, particularly follicular rupture, but not follicle growth or luteinization.Upper panels show ovary sections from mice heterozygous or for PGR that were treated with PMSG to stimulate preovulatory follicle growth. Lower panels show ovary sections from mice treated with PMSG followed by hCG for 48h to stimulate ovulation and luteinization. Lower right panel shows that in PRKO mice, oocytes remain trapped within luteinized follicles. (Reprinted with permission from Robker et al., 2000).

Mentions: Targeted deletion of the PGR gene in mice, the PRKO (progesterone receptor knockout) model, has allowed definition of the specific and direct role of PGR in female fertility [Lydon et al., 1995]. PRKO homozygous females develop normally to adulthood, but the ovaries, uterus, mammary gland and brain exhibit altered phenotypes, demonstrating that PGR exerts pleiotropic control over reproductive tissues [Lydon et al., 1996; Lydon et al., 1995]. Within the ovary of PRKO mice there is normal growth and development of ovarian follicles until the preovulatory stage. However, the mice exhibit profound and complete anovulation, even in response to hyperstimulation with gonadotropins, resulting in oocytes retained in unruptured follicles (Figure 3) [Lydon et al., 1995; Robker and Richards, 2000]. Despite impaired follicular rupture, granulosa cells from preovulatory follicles of PRKO mice respond to the LH surge, as demonstrated by the presence of cumulus expansion [Lydon et al., 1995]; normal LH-induced upregulation of COX-2 (cyclooxygenase-2), an enzyme that catalyzes prostaglandin production and is essential for ovulation [Robker et al., 2000]; and differentiation into a luteal phenotype assessed by normal expression of the luteal marker P450 side-chain cleavage enzyme [Robker et al., 2000]. Therefore, PGR is not required for follicle growth and development or granulosa cell differentiation or luteinization, but is specifically and absolutely required for rupture of the preovulatory follicle and oocyte release.


Control of oocyte release by progesterone receptor-regulated gene expression.

Robker RL, Akison LK, Russell DL - Nucl Recept Signal (2009)

Mice  for PGR (PRKO) demonstrate that PGR is essential for ovulation, particularly follicular rupture, but not follicle growth or luteinization.Upper panels show ovary sections from mice heterozygous or  for PGR that were treated with PMSG to stimulate preovulatory follicle growth.  Lower panels show ovary sections from mice treated with PMSG followed by hCG for 48h to stimulate ovulation and luteinization.  Lower right panel shows that in PRKO mice, oocytes remain trapped within luteinized follicles.  (Reprinted with permission from Robker et al., 2000).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2807638&req=5

fig3: Mice for PGR (PRKO) demonstrate that PGR is essential for ovulation, particularly follicular rupture, but not follicle growth or luteinization.Upper panels show ovary sections from mice heterozygous or for PGR that were treated with PMSG to stimulate preovulatory follicle growth. Lower panels show ovary sections from mice treated with PMSG followed by hCG for 48h to stimulate ovulation and luteinization. Lower right panel shows that in PRKO mice, oocytes remain trapped within luteinized follicles. (Reprinted with permission from Robker et al., 2000).
Mentions: Targeted deletion of the PGR gene in mice, the PRKO (progesterone receptor knockout) model, has allowed definition of the specific and direct role of PGR in female fertility [Lydon et al., 1995]. PRKO homozygous females develop normally to adulthood, but the ovaries, uterus, mammary gland and brain exhibit altered phenotypes, demonstrating that PGR exerts pleiotropic control over reproductive tissues [Lydon et al., 1996; Lydon et al., 1995]. Within the ovary of PRKO mice there is normal growth and development of ovarian follicles until the preovulatory stage. However, the mice exhibit profound and complete anovulation, even in response to hyperstimulation with gonadotropins, resulting in oocytes retained in unruptured follicles (Figure 3) [Lydon et al., 1995; Robker and Richards, 2000]. Despite impaired follicular rupture, granulosa cells from preovulatory follicles of PRKO mice respond to the LH surge, as demonstrated by the presence of cumulus expansion [Lydon et al., 1995]; normal LH-induced upregulation of COX-2 (cyclooxygenase-2), an enzyme that catalyzes prostaglandin production and is essential for ovulation [Robker et al., 2000]; and differentiation into a luteal phenotype assessed by normal expression of the luteal marker P450 side-chain cleavage enzyme [Robker et al., 2000]. Therefore, PGR is not required for follicle growth and development or granulosa cell differentiation or luteinization, but is specifically and absolutely required for rupture of the preovulatory follicle and oocyte release.

Bottom Line: The cellular mechanisms by which PGR regulates ovulation are currently under investigation, with several downstream pathways having been identified as PGR-regulated and potentially involved in follicular rupture.Interestingly, none of these PGR-regulated genes has been demonstrated to be a direct transcriptional target of PGR.Rather, in ovarian granulosa cells, PGR may act as an inducible coregulator for constitutively bound Sp1/Sp3 transcription factors, which are key regulators for a discrete cohort of ovulatory genes.

View Article: PubMed Central - PubMed

Affiliation: The Robinson Institute, School of Paediatrics and Reproductive Health, University of Adelaide, SA, Australia. rebecca.robker@adelaide.edu.au

ABSTRACT
The progesterone receptor (PGR) is a nuclear receptor transcription factor that is essential for female fertility, in part due to its control of oocyte release from the ovary, or ovulation. In all mammals studied to date, ovarian expression of PGR is restricted primarily to granulosa cells of follicles destined to ovulate. Granulosa cell expression of PGR is induced by the pituitary Luteinizing Hormone (LH) surge via mechanisms that are not entirely understood, but which involve activation of Protein Kinase A and modification of Sp1/Sp3 transcription factors on the PGR promoter. Null mutations for PGR or treatment with PGR antagonists block ovulation in all species analyzed, including humans. The cellular mechanisms by which PGR regulates ovulation are currently under investigation, with several downstream pathways having been identified as PGR-regulated and potentially involved in follicular rupture. Interestingly, none of these PGR-regulated genes has been demonstrated to be a direct transcriptional target of PGR. Rather, in ovarian granulosa cells, PGR may act as an inducible coregulator for constitutively bound Sp1/Sp3 transcription factors, which are key regulators for a discrete cohort of ovulatory genes.

Show MeSH
Related in: MedlinePlus