Spatiotemporal cellular map of the developing human reproductive tract
Valentina Lorenzi, Cecilia Mazzeo, Charlotte Cassie, Nadav Yayon, Elias R. Ruiz-Morales, Carmen Sancho‐Serra, Ryan Colligan, Frederick C.K. Wong, Magda Marečková, Elizabeth Tuck, Kenny Roberts, Tong Li, Marc‐Antoine Jacques, James Ashcroft, Xiaoling He, Berta Crespo, Batuhan Çakır, Simon Murray, Yong Gu, Alexander V. Predeus, Martin Prete, Iva Kelava, Roger A. Barker, Luz García‐Alonso, John C. Marioni, Roser Vento‐Tormo
Abstract
. Here we present an extensive single-cell and spatial multi-omic atlas of the human reproductive tract during prenatal development to provide insights beyond those that are possible with smaller-scale, organ-focused studies. We describe potential regulators of sexual dimorphism in reproductive organs and pinpoint previously unknown genes involved in Müllerian duct emergence and regression and urethral canalization of the penis. By combining histological features with gene expression and chromatin accessibility data, we define transcription factors and signalling events potentially involved in the regionalization of the Müllerian and Wolffian ducts. We also refine how the HOX code is established in distinct reproductive organs and reveal that the expression of thoracic HOX genes is increased in the rostral mesenchyme of the fallopian tube and epididymis. Our findings further indicate that epithelial regionalization of the fallopian tube and epididymis, which probably contribute to sperm maturation and capacitation, is established during development. By contrast, later events are necessary for regionalization of the uterocervical canal epithelium. Finally, on the basis of single-cell data and fetal-derived organoids, we show that the fetal uterine epithelium is vulnerable to oestrogen-mimicking endocrine disruptors. By mapping sex-specific reproductive tract regionalization and differentiation at the cellular level, our study provides valuable insights into causes and potential treatments of developmental reproductive disorders.