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Postnatal Ovarian Transdifferentiation in the Absence of Estrogen Receptor Signaling Is Dependent on Genetic
April K Binder1,2,3, Katherine A Burns3,4, Karina F Rodriguez3
1Department of Biological Sciences, Central Washington University, Ellensburg, WA 98926, USA.
Abstract:
Normal ovarian function requires the expression of estrogen receptors α (ESR1) and β (ESR2) in distinct cell types within the ovary. The double estrogen receptor knockout (αβERKO) ovary had the appearance of seminiferous tubule-like structures that expressed SOX9; this phenotype was lost when the animals were repeatedly backcrossed to the C57BL/6J genetic background. A new line of ERKO mice, Ex3αβERKO, was developed for targeted disruption on a mixed genetic background. Histological examination of the ovaries in the Ex3αβERKO showed the appearance of seminiferous tubule-like structures in mice aged 6 to 12 months. These dismorphogenic regions have cells that no longer express granulosa cell-specific FOXL2, while other cells express Sertoli cell-specific SOX9 as examined by immunohistochemistry. Whole ovarian gene expression analysis in Ex3αERKO, Ex3βRKO, and Ex3αβERKO found many genes differentially expressed compared to controls with one Esr1 and Esr2 allele. The genes specific to the Ex3αβERKO ovary were compared to other models of postnatal ovarian transdifferentiation, identifying 21 candidate genes. To examine the genetic background contributions, DNA was isolated from αβERKO mice that did not show ovarian transdifferentiation and compared to DNA from Ex3αβERKO using Mouse Diversity Array. A genomic region putatively associated with transdifferentiation was identified on Chr18 (5-15 M) and genes in this region were compared to the genes differentially expressed in models of ovarian transdifferentiation. This work demonstrates the importance of ESRs in maintaining granulosa cell differentiation within the ovary, identifies several potential gene candidates, and suggests that genetic background can be a confounding factor.
Insights
Estrogen receptors alpha and beta (ESR1, ESR2) are crucial for normal ovarian function. Their absence can lead to ovarian transdifferentiation, a process influenced by genetic background.
Area of Science:
- Reproductive Biology
- Endocrinology
- Genetics
Background:
- Normal ovarian function depends on distinct expression of estrogen receptors alpha (ESR1) and beta (ESR2).
- Ovarian transdifferentiation, characterized by seminiferous tubule-like structures and altered cell markers (loss of FOXL2, gain of SOX9), was observed in double estrogen receptor knockout (αβERKO) ovaries.
- This phenotype was lost in mice backcrossed to a pure C57BL/6J background, suggesting genetic background influence.
Purpose of the Study:
- To investigate the role of estrogen receptors in maintaining ovarian granulosa cell differentiation.
- To identify candidate genes involved in postnatal ovarian transdifferentiation.
- To explore the impact of genetic background on ovarian development and estrogen receptor function.
Main Methods:
- Development of a new ERKO mouse line (Ex3αβERKO) on a mixed genetic background.
- Histological and immunohistochemical analysis of ovaries to examine cell morphology and marker expression (FOXL2, SOX9).
- Whole ovarian gene expression analysis and comparison with other transdifferentiation models.
- DNA analysis using Mouse Diversity Array to identify genetic background contributions.
Main Results:
- Ex3αβERKO mice aged 6-12 months exhibited ovarian seminiferous tubule-like structures with FOXL2-negative and SOX9-positive cells.
- Significant differential gene expression was observed in Ex3αERKO, Ex3βRKO, and Ex3αβERKO ovaries compared to controls.
- 21 candidate genes were identified by comparing Ex3αβERKO specific genes with other postnatal ovarian transdifferentiation models.
- A genomic region on Chr18 (5-15 M) was putatively associated with transdifferentiation, highlighting genetic background effects.
Conclusions:
- Estrogen receptors (ESRs) are essential for maintaining granulosa cell differentiation in the ovary.
- Several candidate genes potentially mediate ovarian transdifferentiation.
- Genetic background is a critical confounding factor in studies of ovarian development and estrogen receptor function.
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