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

Martín Andrés Estermann, Sara A. Grimm, Abigail S. Kitakule, Karina F. Rodriguez, Paula R. Brown, Kathryn McClelland, Ciro M. Amato and Humphrey Hung-Chang Yao ()
Additional contact information
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
Humphrey Hung-Chang Yao: Research Triangle Park

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-025-59183-6 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-59183-6

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-025-59183-6

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().