Pluripotency of male germ cells must be tightly balanced during embryonic development: sufficient numbers of pluripotent stem cells must be allocated for fertility, but unconstrained pluripotency gives rise to cancer precursors.
Nodal/Cripto is a classical developmental signaling pathway that also controls pluripotency in ES cells and is overexpressed in many cancers. Our studies in mice identified the Nodal co-receptor Cripto as controlling pluripotency of fetal male germ cells during the time in which they are particularly susceptible to malignant transformation. To explore the relationship between correct fetal germ cell pluripotency/differentiation and tumorigenesis we are investigating germ cell-specific, single and combined, Nodal/Cripto gain- and loss- of function transgenic mouse models.
When Nodal/Cripto signaling is suppressed in fetal germ cells, we find germline pluripotency is decreased and that Cripto can signal independently of Nodal and vice versa. In our mouse model of Cripto-overexpressing germ cells we find that spermatogonial stem cells are still specified, but these cells fail to undergo spermatogenesis and retain a stem cell like state. I will present our recent work in which we analyse the role of Cripto signaling in both fetal and neonatal germline development and discuss the implications for fertility and disease.