Neumann, Michelle;
(2023)
The role of FOXL2 in the maintenance of ovarian cell fate.
Doctoral thesis (Ph.D), UCL (University College London).
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Abstract
Gonad identity in mice is dependent on specification of bipotential precursor cells into granulosa cells of the ovary or Sertoli cells of the testis during sex determination at E11.5. However, deletion of Foxl2 in 8-week-old females results in gonadal sex reversal, where granulosa cells destabilise their fate and transdifferentiate into Sertoli-like cells. This involves activation of the testis-specific transcription factor SOX9, indicating that FOXL2 directly represses Sox9 in the ovary. Here, the aim was to understand molecular and regulatory mechanisms underlying the ability of ovarian cells to transdifferentiate into testicular cell types. To investigate the period during which ovaries are permissive for the cell fate switch, Foxl2 was conditionally inactivated at different embryonic and postnatal stages, including pre and post pregnancy to investigate whether hormonal changes experienced during pregnancy impede somatic sex reprogramming. This revealed that extensive gonadal sex reversal is inducible at all timepoints, except in the embryo, where it is only partial, showing how FOXL2 becomes critical for maintaining ovarian cell fate postnatally. To explore the transcriptional changes occurring in the ovary upon deletion of Foxl2, scRNA-Seq was performed on dissociated cells from testes and ovaries collected before, during and after gonadal sex reversal. This resolved cell composition and provided evidence for a direct transdifferentiation trajectory from granulosa into Sertoli cells. A Foxl2GFP reporter mouse strain was also developed using CRISPR-Cas9, which was utilised to identify changes in chromatin accessibility specifically in isolated FOXL2-positive supporting cells. It was discovered that XX Foxl2cKO gonads display a testis-like chromatin accessibility landscape with closing of ovary- and opening of testis-biased chromatin regions. Moreover, several regions upstream of Sox9 were identified that might play a role in FOXL2-dependent Sox9 repression in ovaries. These studies provide an important advance in understanding the molecular and regulatory mechanisms underlying granulosa and ovarian cell fate maintenance.
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | Ph.D |
| Title: | The role of FOXL2 in the maintenance of ovarian cell fate |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| Additional information: | Copyright © The Author 2023. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10174084 |
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