Proc Natl Acad Sci U S A. 2026 Oct 6;123(40):e2615939123. doi: 10.1073/pnas.2615939123. Epub 2026 Sep 28.
Spatiotemporally primed coelomic epithelium and supporting-like cells establish the dual origin of granulosa cells
Cyril Djari#1,2, Chloé Mayère#1,2, Maëva Guy1,2, Aitana Perea-Gomez3, Laura Bellutti4,5, Paul Barreau1,2, Herta Ademi1,2, Agathe Rozier3, Anthony S Martinez6, Tyler J Gibson6, Françoise Kühne1,2, Cassandre Guérin3, Dagmar Wilhelm7, Gabriel Livera4,5, Jennifer McKey6, Marie-Christine Chaboissier3, Serge Nef1,2
Affiliations
1Department of Genetic Medicine and Development, University of Geneva, Geneva 1211, Switzerland.
2Institute of Genetics and Genomics in Geneva, Institute of Genetics and Genomics of Geneva, University of Geneva, Geneva 1211, Switzerland.
3Université Côte d’Azur, CNRS, Inserm, Institut de Biologie Valrose, Nice 06108, France.
4University Paris Cité, Inserm, French Alternative Energies and Atomic Energy Commission, Genetic Stability Stem Cells and Radiation, Laboratory of Development of the Gonads, Université Paris Cité, Fontenay-aux-Roses F-92265, France.
5University Paris Cité, Inserm, French Alternative Energies and Atomic Energy Commission, Genetic Stability Stem Cells and Radiation, Genetic Stability, Stem Cells and Radiation, Laboratory of Development of the Gonads/Institute of Cellular and Molecular Radiobiology/François Jacob Institute of Biology, Université Paris-Saclay, Fontenay-aux-Roses F-92265, France.
6Section of Developmental Biology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
7Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC 3010, Australia.
#Contributed equally.
Abstract
Ovarian organogenesis relies on the coordinated specification of supporting and steroidogenic lineages from multipotent progenitors of the coelomic epithelium. However, how these progenitors adopt distinct fates and differentiate into pregranulosa cells and steroidogenic progenitors of theca cells remain poorly understood. Here, we show that the dynamics of ovarian somatic lineage specification are conserved between human and mouse. Coelomic epithelial cells covering the fetal ovaries are heterogeneous and already biased toward supporting or steroidogenic fates. This priming is spatially and temporally organized, influenced by proximity to the mesonephros, and characterized by a transient coexistence of both progenitor types before resolving into predominantly supporting-biased cells. In mice, local delamination of these primed epithelial progenitors seeds intragonadal domains that give rise to pregranulosa and steroidogenic progenitors. We further demonstrate that these fetal steroidogenic progenitors generate adult stromal and theca cells. In addition, we uncover that granulosa cells arise from two distinct sources: Coelomic epithelium-derived progenitors generate the majority of cortical granulosa cells forming the long-lived follicle reserve, whereas supporting-like cells contribute to a smaller granulosa subpopulation. Together, these findings establish a revised model of ovarian development in which early spatial patterning of coelomic epithelial progenitors directs lineage specification, reveals the dual origin of granulosa cells, and defines the developmental origin of theca cells.