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
    ---><---

    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.

    We have no bibliographic references for this item. You can help adding them by using 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.