FOXL2 Interaction with Different Binding Partners Regulates the Dynamics of Ovarian Development

Overview

Journal Sci Adv

Specialties Biology
Science

Date 2024 Mar 22

PMID 38517962

Authors

Roberta Migale

Michelle Neumann

Richard Mitter

Mahmoud-Reza Rafiee

Sophie Wood

Jessica Olsen

Robin Lovell-Badge

Affiliations

Soon will be listed here.

Abstract

The transcription factor FOXL2 is required in ovarian somatic cells for female fertility. Differential timing of deletion, in embryonic versus adult mouse ovary, leads to distinctive outcomes, suggesting different roles across development. Here, we comprehensively investigated FOXL2's role through a multi-omics approach to characterize gene expression dynamics and chromatin accessibility changes, coupled with genome-wide identification of FOXL2 targets and on-chromatin interacting partners in somatic cells across ovarian development. We found that FOXL2 regulates more targets postnatally, through interaction with factors regulating primordial follicle formation and steroidogenesis. Deletion of one interactor, ubiquitin-specific protease 7 (), results in impairment of somatic cell differentiation, germ cell nest breakdown, and ovarian development, leading to sterility. Our datasets constitute a comprehensive resource for exploration of the molecular mechanisms of ovarian development and causes of female infertility.

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References

Uda M, Ottolenghi C, Crisponi L, Garcia J, Deiana M, Kimber W . Foxl2 disruption causes mouse ovarian failure by pervasive blockage of follicle development. Hum Mol Genet. 2004; 13(11):1171-81. DOI: 10.1093/hmg/ddh124. View

Koentgen F, Lin J, Katidou M, Chang I, Khan M, Watts J . Exclusive transmission of the embryonic stem cell-derived genome through the mouse germline. Genesis. 2016; 54(6):326-33. PMC: 5084746. DOI: 10.1002/dvg.22938. View

Koopman P, Gubbay J, Vivian N, Goodfellow P, Lovell-Badge R . Male development of chromosomally female mice transgenic for Sry. Nature. 1991; 351(6322):117-21. DOI: 10.1038/351117a0. View

Efimenko E, Padua M, Manuylov N, Fox S, Morse D, Tevosian S . The transcription factor GATA4 is required for follicular development and normal ovarian function. Dev Biol. 2013; 381(1):144-58. PMC: 4089064. DOI: 10.1016/j.ydbio.2013.06.004. View

Morris M, Meinsohn M, Chauvin M, Saatcioglu H, Kashiwagi A, Sicher N . A single-cell atlas of the cycling murine ovary. Elife. 2022; 11. PMC: 9545525. DOI: 10.7554/eLife.77239. View

Kim S, Park J, Spring C, Sater A, Ji H, Otchere A . Non-canonical Wnt signals are modulated by the Kaiso transcriptional repressor and p120-catenin. Nat Cell Biol. 2004; 6(12):1212-20. DOI: 10.1038/ncb1191. View

Lindeman R, Murphy M, Agrimson K, Gewiss R, Bardwell V, Gearhart M . The conserved sex regulator DMRT1 recruits SOX9 in sexual cell fate reprogramming. Nucleic Acids Res. 2021; 49(11):6144-6164. PMC: 8216462. DOI: 10.1093/nar/gkab448. View

Kreidberg J, Sariola H, LORING J, Maeda M, Pelletier J, Housman D . WT-1 is required for early kidney development. Cell. 1993; 74(4):679-91. DOI: 10.1016/0092-8674(93)90515-r. View

Herman L, Legois B, Todeschini A, Veitia R . Genomic exploration of the targets of FOXL2 and ESR2 unveils their implication in cell migration, invasion, and adhesion. FASEB J. 2021; 35(4):e21355. DOI: 10.1096/fj.202002444R. View

10.

De Gendt K, Swinnen J, Saunders P, Schoonjans L, Dewerchin M, Devos A . A Sertoli cell-selective knockout of the androgen receptor causes spermatogenic arrest in meiosis. Proc Natl Acad Sci U S A. 2004; 101(5):1327-32. PMC: 337052. DOI: 10.1073/pnas.0308114100. View

11.

Rafiee M, Girardot C, Sigismondo G, Krijgsveld J . Expanding the Circuitry of Pluripotency by Selective Isolation of Chromatin-Associated Proteins. Mol Cell. 2016; 64(3):624-635. PMC: 5101186. DOI: 10.1016/j.molcel.2016.09.019. View

12.

Wu T, Hu E, Xu S, Chen M, Guo P, Dai Z . clusterProfiler 4.0: A universal enrichment tool for interpreting omics data. Innovation (Camb). 2021; 2(3):100141. PMC: 8454663. DOI: 10.1016/j.xinn.2021.100141. View

13.

Wang D, Kobayashi T, Zhou L, Paul-Prasanth B, Ijiri S, Sakai F . Foxl2 up-regulates aromatase gene transcription in a female-specific manner by binding to the promoter as well as interacting with ad4 binding protein/steroidogenic factor 1. Mol Endocrinol. 2006; 21(3):712-25. DOI: 10.1210/me.2006-0248. View

14.

Englert C, Vidal M, Maheswaran S, Ge Y, Ezzell R, Isselbacher K . Truncated WT1 mutants alter the subnuclear localization of the wild-type protein. Proc Natl Acad Sci U S A. 1995; 92(26):11960-4. PMC: 40275. DOI: 10.1073/pnas.92.26.11960. View

15.

Bandiera R, Vidal V, Motamedi F, Clarkson M, Sahut-Barnola I, von Gise A . WT1 maintains adrenal-gonadal primordium identity and marks a population of AGP-like progenitors within the adrenal gland. Dev Cell. 2013; 27(1):5-18. PMC: 4032791. DOI: 10.1016/j.devcel.2013.09.003. View

16.

Rodriguez K, Brown P, Amato C, Nicol B, Liu C, Xu X . Somatic cell fate maintenance in mouse fetal testes via autocrine/paracrine action of AMH and activin B. Nat Commun. 2022; 13(1):4130. PMC: 9287316. DOI: 10.1038/s41467-022-31486-y. View

17.

Cam H, Whitehall S . Chromatin Immunoprecipitation (ChIP) in Schizosaccharomyces pombe. Cold Spring Harb Protoc. 2016; 2016(11). DOI: 10.1101/pdb.prot091546. View

18.

Machlab D, Burger L, Soneson C, Rijli F, Schubeler D, Stadler M . monaLisa: an R/Bioconductor package for identifying regulatory motifs. Bioinformatics. 2022; 38(9):2624-2625. PMC: 9048699. DOI: 10.1093/bioinformatics/btac102. View

19.

Schmidt D, Ovitt C, Anlag K, Fehsenfeld S, Gredsted L, Treier A . The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development. 2004; 131(4):933-42. DOI: 10.1242/dev.00969. View

20.

Ross-Innes C, Stark R, Teschendorff A, Holmes K, Ali H, Dunning M . Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature. 2012; 481(7381):389-93. PMC: 3272464. DOI: 10.1038/nature10730. View