Contrary to their somatic counterparts, primordial germ cells (PGCs) maintain an active pluripotency network and can give rise to any cell types. Following migration to the developing male gonad, the PGC pluripotency program is progressively shut down as they commit to the pro-spermatogonia fate during a short developmental window (E11.5 to E14.5). PGCs that fail to differentiate, by maintaining pluripotency, harbour malignant potential and are considered the origin of testicular germ cell tumours in humans.
We aimed to explore the role of Cripto in this developmental process. Cripto is a co-receptor for Nodal signalling and is initially expressed in PGCs until E11.5, when its expression decreases as PGCs lose pluripotency. Because we found that CRIPTO is overexpressed in pluripotent human testicular germ cell tumours (incl. seminomas, embryonic carcinoma), we hypothesised that maintenance of Cripto expression in PGCs might drive malignant transformation.
We generated a novel, germ cell specific, CRE recombinase mouse line (Ddx4-iCre) to over-express Cripto in PGCs from E11.5. We found that Cripto overexpression in PGCs leads to the maintenance of a pluripotent state. Furthermore, Cripto-overexpressing (Cripto-OE) PGCs failed to correctly differentiate, leading to germ cell depletion by the time of birth. Although the Cripto-OEPGC model held great potential to replicate the human pathology of testicular germ cell tumours, the complete lack of germ cells in Cripto-OEPGC adult mice hindered our ability to investigate whether testicular tumours would form. To circumvent the germ cell loss, we placed our Cripto-OE model on a BAX-KO background (Bax is a pro-apoptotic gene). Here, as early as 8 weeks of age, we observed Cripto-OE germ cells persisting in homogenous clusters that morphologically resemble human intra-tubular seminomas.
Altogether, we propose an oncogenic role for Cripto in the context of PGC development and present a possible novel mouse model of seminoma germ cell tumours.