Nodal Signaling Regulates Germ Cell Development and Establishment of Seminiferous Cords in the Human Fetal Testis

Disruption of human fetal testis development is widely accepted to underlie testicular germ cell cancer (TGCC) origin and additional disorders within testicular dysgenesis syndrome (TDS). However, the mechanisms for the development of testicular dysgenesis in humans are unclear. We used ex vivo culture and xenograft approaches to investigate the importance of Nodal and Activin signaling in human fetal testis development. Inhibition of Nodal, and to some extent Activin, signaling disrupted seminiferous cord formation, abolished AMH expression, reduced androgen secretion, and decreased gonocyte numbers. Subsequent xenografting of testicular tissue rescued the disruptive effects on seminiferous cords and somatic cells but not germ cell effects. Stimulation of Nodal signaling increased the number of germ cells expressing pluripotency factors, and these persisted after xenografting. Our findings suggest a key role for Nodal signaling in the regulation of gonocyte differentiation and early human testis development with implications for the understanding of TGCC and TDS origin. [Display omitted] •Nodal and Activin signaling was manipulated during human testicular development•Inhibiting Nodal/Activin signaling results in testicular dysgenesis and gonocyte loss•Effects on somatic cell lineages and testicular morphology are rescued with time•Nodal pathway stimulation results in persisting gonocytes resembling TGCC precursors Jørgensen et al. determine the role of Nodal signaling in human fetal testis development using ex vivo culture and xenografting approaches. They provide insights into the involvement of Nodal signaling in seminiferous cord formation and the regulation of pluripotency factor expression in fetal gonocytes, with implications for the development of testicular cancer.