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A Hyperandrogenic Mouse Model to Study Polycystic Ovary Syndrome
Published on: October 2, 2018
Selective deletion of Pten in theca-interstitial cells leads to androgen excess and ovarian dysfunction in mice
Zi-Jian Lan1, M S Krause2, S D Redding2
1Division of Life Sciences and Center for Animal Nutrigenomics & Applied Animal Nutrition, Alltech Inc., Nicholasville, KY 40356, USA.
Abstract:
Theca cell-selective Pten mutation (tPtenMT) in mice resulted in increases in PDK1 and Akt phosphorylation, indicating an over-activation of PI3K signaling in the ovaries. These mice displayed elevated androgen levels, ovary enlargement, antral follicle accumulation, early fertility loss and increased expression of Lhcgr and genes that are crucial to androgenesis. These abnormalities were partially reversed by treatments of PI3K or Akt inhibitor. LH actions in Pten deficient theca cells were potentiated. The phosphorylation of Foxo1 was increased, while the binding of Foxo1 to forkhead response elements in the Lhcgr promoter was reduced in tPtenMT theca cells, implying a mechanism by which PI3K/Akt-induced upregulation of Lhcgr in theca cells might be mediated by reducing the inhibitory effect of Foxo1 on the Lhcgr promoter. The phenotype of tPtenMT females is reminiscent of human PCOS and suggests that dysregulated PI3K cascade in theca cells may be involved in certain types of PCOS pathogenesis.
Insights
Genetic alterations in ovarian theca cells (tPtenMT) led to overactive PI3K signaling, causing hormonal imbalances and fertility issues in mice, mimicking human PCOS. Inhibitor treatments partially reversed these effects.
Area of Science:
- Reproductive Endocrinology
- Molecular Biology
- Genetics
Background:
- The phosphoinositide 3-kinase (PI3K)/Akt signaling pathway plays a critical role in ovarian function.
- Dysregulation of this pathway is implicated in various reproductive disorders.
Purpose of the Study:
- To investigate the role of Pten in theca cell function and its potential link to Polycystic Ovary Syndrome (PCOS) pathogenesis.
- To elucidate the molecular mechanisms by which Pten deficiency affects ovarian physiology.
Main Methods:
- Generation of theca cell-specific Pten-mutant (tPtenMT) mice.
- Biochemical analysis of signaling pathways (PDK1, Akt, Foxo1 phosphorylation).
- Assessment of ovarian morphology, hormone levels, fertility, and gene expression (Lhcgr, androgenesis genes).
- Pharmacological inhibition of PI3K and Akt pathways.
Main Results:
- tPtenMT mice exhibited hyperactivated PI3K/Akt signaling in ovarian theca cells.
- These mice showed elevated androgens, ovarian enlargement, follicle accumulation, and premature fertility loss.
- Abnormalities were partially ameliorated by PI3K or Akt inhibitors, indicating pathway involvement.
- Pten deficiency potentiated LH actions and altered Foxo1 binding to the Lhcgr promoter, suggesting a novel regulatory mechanism.
Conclusions:
- Dysregulated PI3K signaling in theca cells, driven by Pten mutation, contributes to PCOS-like phenotypes in mice.
- The findings highlight a potential mechanism involving Foxo1 and Lhcgr regulation in theca cells.
- This study provides insights into the pathogenesis of certain PCOS types and identifies potential therapeutic targets.
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