IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-59183-6.html
   My bibliography  Save this article

NR2F2 regulation of interstitial cell fate in the embryonic mouse testis and its impact on differences of sex development

Author

Listed:
  • Martín Andrés Estermann

    (Research Triangle Park)

  • Sara A. Grimm

    (Research Triangle Park)

  • Abigail S. Kitakule

    (Research Triangle Park)

  • Karina F. Rodriguez

    (Research Triangle Park)

  • Paula R. Brown

    (Research Triangle Park)

  • Kathryn McClelland

    (Research Triangle Park)

  • Ciro M. Amato

    (Research Triangle Park
    University of Missouri)

  • Humphrey Hung-Chang Yao

    (Research Triangle Park)

Abstract

Testicular fetal Leydig cells produce androgens essential for male reproductive development. Impaired fetal Leydig cell differentiation leads to differences of sex development including hypospadias, cryptorchidism, and infertility. Despite fetal Leydig cells are thought to originate from proliferating progenitor cells in the testis interstitium, the precise mechanisms governing the interstitial cells to fetal Leydig cell transition remain elusive. Using mouse models and single-nucleus multiomics, we find that fetal Leydig cells arise from a Nr2f2-positive interstitial population. Embryonic deletion of Nr2f2 in mouse testes results in differences of sex development, including dysgenic testes, Leydig cell hypoplasia, cryptorchidism, and hypospadias. By combining single-nucleus multiomics and NR2F2 ChIP-seq we find that NR2F2 promotes the progenitor fate while suppresses Leydig cell differentiation by modulating key transcription factors and downstream genes. Our findings establish Nr2f2 as a crucial regulator of fetal Leydig cell differentiation and provide molecular insights into differences of sex development linked to Nr2f2 mutations.

Suggested Citation

  • Martín Andrés Estermann & Sara A. Grimm & Abigail S. Kitakule & Karina F. Rodriguez & Paula R. Brown & Kathryn McClelland & Ciro M. Amato & Humphrey Hung-Chang Yao, 2025. "NR2F2 regulation of interstitial cell fate in the embryonic mouse testis and its impact on differences of sex development," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59183-6
    DOI: 10.1038/s41467-025-59183-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-59183-6
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-59183-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Luz Garcia-Alonso & Valentina Lorenzi & Cecilia Icoresi Mazzeo & João Pedro Alves-Lopes & Kenny Roberts & Carmen Sancho-Serra & Justin Engelbert & Magda Marečková & Wolfram H. Gruhn & Rachel A. Bottin, 2022. "Single-cell roadmap of human gonadal development," Nature, Nature, vol. 607(7919), pages 540-547, July.
    2. Yu-chi Shen & Adrienne Niederriter Shami & Lindsay Moritz & Hailey Larose & Gabriel L. Manske & Qianyi Ma & Xianing Zheng & Meena Sukhwani & Michael Czerwinski & Caleb Sultan & Haolin Chen & Stephen J, 2021. "TCF21+ mesenchymal cells contribute to testis somatic cell development, homeostasis, and regeneration in mice," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    3. Deepti L. Kumar & Tony DeFalco, 2018. "A perivascular niche for multipotent progenitors in the fetal testis," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Denis Houzelstein & Caroline Eozenou & Carlos F. Lagos & Maëva Elzaiat & Joelle Bignon-Topalovic & Inma Gonzalez & Vincent Laville & Laurène Schlick & Somboon Wankanit & Prochi Madon & Jyotsna Kirtane, 2024. "A conserved NR5A1-responsive enhancer regulates SRY in testis-determination," Nature Communications, Nature, vol. 15(1), pages 1-12, December.
    2. Chao-Hui Chang & Feng Liu & Stefania Militi & Svenja Hester & Reshma Nibhani & Siwei Deng & James Dunford & Aniko Rendek & Zahir Soonawalla & Roman Fischer & Udo Oppermann & Siim Pauklin, 2024. "The pRb/RBL2-E2F1/4-GCN5 axis regulates cancer stem cell formation and G0 phase entry/exit by paracrine mechanisms," Nature Communications, Nature, vol. 15(1), pages 1-29, December.
    3. Shuangsang Fang & Mengyang Xu & Lei Cao & Xiaobin Liu & Marija Bezulj & Liwei Tan & Zhiyuan Yuan & Yao Li & Tianyi Xia & Longyu Guo & Vladimir Kovacevic & Junhou Hui & Lidong Guo & Chao Liu & Mengnan , 2025. "Stereopy: modeling comparative and spatiotemporal cellular heterogeneity via multi-sample spatial transcriptomics," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    4. Hao Li & Meng-Jie Zhang & Boxin Zhang & Wen-Ping Lin & Shu-Jin Li & Dian Xiong & Qing Wang & Wen-Da Wang & Qi-Chao Yang & Cong-Fa Huang & Wei-Wei Deng & Zhi-Jun Sun, 2025. "Mature tertiary lymphoid structures evoke intra-tumoral T and B cell responses via progenitor exhausted CD4+ T cells in head and neck cancer," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    5. Mingze Dong & David G. Su & Harriet Kluger & Rong Fan & Yuval Kluger, 2025. "SIMVI disentangles intrinsic and spatial-induced cellular states in spatial omics data," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    6. Shi-Han Yang & Si-Ting Chen & Chen Liang & Yong-Hong Shi & Qiu-Sheng Chen, 2022. "Effects of Cadmium Exposure on Leydig Cells and Blood Vessels in Mouse Testis," IJERPH, MDPI, vol. 19(4), pages 1-13, February.
    7. Chanu, Athokpam Langlen & Singh, R.K. Brojen & Jeon, Jae-Hyung, 2024. "Exploring the interplay of intrinsic fluctuation and complexity in intracellular calcium dynamics," Chaos, Solitons & Fractals, Elsevier, vol. 185(C).
    8. Brianna R. Watson & Biplab Paul & Raza Ur Rahman & Liat Amir-Zilberstein & Åsa Segerstolpe & Eliana T. Epstein & Shane Murphy & Ludwig Geistlinger & Tyrone Lee & Angela Shih & Jacques Deguine & Ramnik, 2025. "Spatial transcriptomics of healthy and fibrotic human liver at single-cell resolution," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    9. Ani Chi & Bicheng Yang & Hao Dai & Xinyu Li & Jiahui Mo & Yong Gao & Zhihong Chen & Xin Feng & Menghui Ma & Yanqing Li & Chao Yang & Jie Liu & Hanchao Liu & Zhenqing Wang & Feng Gao & Yan Liao & Xueta, 2024. "Stem Leydig cells support macrophage immunological homeostasis through mitochondrial transfer in mice," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    10. Ankit Agrawal & Stefan Thomann & Sukanya Basu & Dominic Grün, 2024. "NiCo identifies extrinsic drivers of cell state modulation by niche covariation analysis," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    11. Gefei Wang & Jia Zhao & Yingxin Lin & Tianyu Liu & Yize Zhao & Hongyu Zhao, 2025. "scMODAL: a general deep learning framework for comprehensive single-cell multi-omics data alignment with feature links," Nature Communications, Nature, vol. 16(1), pages 1-13, December.
    12. Klaudija Daugelaite & Perrine Lacour & Ivana Winkler & Marie-Luise Koch & Anja Schneider & Nina Schneider & Francesca Coraggio & Alexander Tolkachov & Xuan Phuoc Nguyen & Adriana Vilkaite & Julia Rehn, 2025. "Granulosa cell transcription is similarly impacted by superovulation and aging and predicts early embryonic trajectories," Nature Communications, Nature, vol. 16(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59183-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.