Decision letter: The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells

Gonadal sexual fate in mammals is determined during embryonic development and must be actively maintained in adulthood. Therefore, gonadal sex-specific transcription factors are required to prevent transdifferentiation of gonadal somatic cells to the other sexual fate. Mouse genetic experiments have shown that oestrogen receptor signalling and the transcription factor FOXL2 protect ovarian granulosa cells from transdifferentiation into Sertoli cells, their testicular counterpart. However, the mechanism underlying this protective mechanism is unknown. Here, we show that one post-translational modification (i.e. SUMOylation catalysed by TRIM28) is sufficient to prevent female-to-male sex reversal of the mouse ovary after birth. We found that upon loss of TRIM28 SUMO-E3 ligase activity, ovarian granulosa cells transdifferentiate to Sertoli cells through an intermediate cell type different from gonadal embryonic progenitors. TRIM28 binds to chromatin close to the critical transcription factor FOXL2 to maintain the female pathway through SUMOylation of specific chromatin regions. Therefore, FOXL2 signalling might maintain the adult ovary cell fate via TRIM28-dependent SUMOylation. Improper SUMOylation of chromatin regions in granulosa cells might lead to female reproductive disorders and infertility, the incidence of which is currently increasing.

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MiR-126* is a novel functional target of transcription factor SMAD4 in ovarian granulosa cells

Gene ◽

10.1016/j.gene.2019.143953 ◽

2019 ◽

Vol 711 ◽

pp. 143953 ◽

Cited By ~ 3

Author(s):

Qiqi Li ◽

Xing Du ◽

Lu Liu ◽

Zengxiang Pan ◽

Shaoxian Cao ◽

...

Keyword(s):

Transcription Factor ◽

Granulosa Cells ◽

Ovarian Granulosa Cells

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The transcription factor SMAD4 and miR-10b contribute to E2 release and cell apoptosis in ovarian granulosa cells by targeting CYP19A1

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2018.04.012 ◽

2018 ◽

Vol 476 ◽

pp. 84-95 ◽

Cited By ~ 14

Author(s):

Qiqi Li ◽

Xing Du ◽

Zengxiang Pan ◽

Lifan Zhang ◽

Qifa Li

Keyword(s):

Transcription Factor ◽

Granulosa Cells ◽

Cell Apoptosis ◽

Ovarian Granulosa Cells

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The transcription factor FOXL2 mobilizes estrogen signaling to maintain the identity of ovarian granulosa cells

eLife ◽

10.7554/elife.04207 ◽

2014 ◽

Vol 3 ◽

Cited By ~ 43

Author(s):

Adrien Georges ◽

David L'Hôte ◽

Anne Laure Todeschini ◽

Aurélie Auguste ◽

Bérangère Legois ◽

...

Keyword(s):

Transcription Factor ◽

Steroid Receptors ◽

Estrogen Receptor Beta ◽

Estrogen Signaling ◽

Follicular Cells ◽

Ovarian Granulosa Cells ◽

Normal Gene ◽

And Function ◽

Receptor Beta

FOXL2 is a lineage determining transcription factor in the ovary, but its direct targets and modes of action are not fully characterized. In this study, we explore the targets of FOXL2 and five nuclear receptors in murine primary follicular cells. We found that FOXL2 is required for normal gene regulation by steroid receptors, and we show that estrogen receptor beta (ESR2) is the main vector of estradiol signaling in these cells. Moreover, we found that FOXL2 directly modulates Esr2 expression through a newly identified intronic element. Interestingly, we found that FOXL2 repressed the testis-determining gene Sox9 both independently of estrogen signaling and through the activation of ESR2 expression. Altogether, we show that FOXL2 mobilizes estrogen signaling to establish a coherent feed-forward loop repressing Sox9. This sheds a new light on the role of FOXL2 in ovarian maintenance and function.

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