Study Maps How Human Reproductive Organs Form

A new study has mapped the cellular landscape of human reproductive organ development, revealing the genes and signals that shape these tissues before birth. Researchers at the Wellcome Sanger Institute and EMBL’s European Bioinformatics Institute (EMBL-EBI) analyzed more than half a million individual cells from developing reproductive systems, producing the most detailed map so far of how these organs form. Published in Nature, the research provides insight into the biological processes that underlie fertility and how environmental influences may affect reproductive health.

Although chromosomal sex is determined at conception, visible differences between male and female reproductive systems appear only around six weeks later. At this early stage, embryos possess undifferentiated gonads and two sets of ducts—the Müllerian and the Wolffian—with the potential to form either female or male internal organs. The SRY gene on the Y chromosome activates testis development, prompting the Wolffian ducts to form male reproductive structures and causing the Müllerian ducts to regress. Without SRY, the gonads become ovaries, and the Müllerian ducts develop into female reproductive organs.

While gonad development has been studied extensively, how the rest of the reproductive tract forms has been less understood. The team examined 89 embryonic and fetal tissue samples using single-cell RNA sequencing, ATAC sequencing, and spatial transcriptomics. Combining these methods allowed them to determine which genes are active in each cell and where those genes operate, showing how the initially identical ducts remodel into distinct organs such as the fallopian tubes, uterus, cervix, and vagina in females, and the epididymis, vas deferens, and seminal vesicle in males.

The researchers identified genes that guide Müllerian duct maturation in females and others that cause its regression in males. Their findings also shed light on formation of the urethra, offering clues to the origins of hypospadias, where the urethra opens partway along the penis. By creating a computational model to follow gene activity along the ducts, the team revealed gradual regional changes that reshape them into specific organs and proposed an updated model for how HOX genes influence this process.

Using organoid models of the developing uterine lining, the study also showed that exposure to bisphenol A and butyl benzyl phthalate activates estrogen-responsive genes.

“For the first time, we can see in detail how the human reproductive system is assembled before birth,” explained co-first author Dr. Valentina Lorenzi. “This map pinpoints the exact cells and signals that shape each organ, and highlights when development is most vulnerable. This is an essential step towards understanding fertility, congenital alterations, and the impact of our environment on reproductive health.”