Role of Nodal signalling in testis development and initiation of testicular cancer

Abstract

Testicular development from the initially bipotential gonad is a tightly regulated process involving a complex signalling cascade to ensure proper sequential expression of signalling factors and secretion of steroid hormones. Initially, Sertoli cell specification facilitates differentiation of the steroidogenic fetal Leydig cells and establishment of the somatic niche, which is critical in supporting the germ cell population. Impairment of the somatic niche during fetal life may lead to development of male reproductive disorders, including arrest of gonocyte differentiation, which is considered the first step in the testicular cancer pathogenesis. In this review, we will outline the signalling pathways involved in fetal testis development focusing on the Nodal pathway, which has recently been implicated in several aspects of testicular differentiation in both mouse and human studies. Nodal signalling plays important roles in germ cell development, including regulation of pluripotency factor expression, proliferation and survival. Moreover, the Nodal pathway is involved in establishment of the somatic niche, including formation of seminiferous cords, steroidogenesis and Sertoli cell function. In our outline of fetal testis development, important differences between human and mouse models will be highlighted to emphasise that information obtained from mouse studies cannot always be directly translated to humans. Finally, the implications of dysregulated Nodal signalling in development of the testicular cancer precursor, germ cell neoplasia in situ, and testicular dysgenesis will be discussed – none of which arise in rodents, emphasising the importance of human models in the effort to increase our understanding of origin and early development of these disorders.

Influence of Nodal signalling on pluripotency factor expression, tumour cell proliferation and cisplatin-sensitivity in testicular germ cell tumours

“…Several independent studies have implicated the Nodal signalling pathway in the pathogenesis of TGCTs [12,[14][15][16][17][18][19]. Recently, we found that stimulation of the Nodal pathway in human fetal testes prolonged the expression of OCT4 in gonocytes, thus directly implicating the pathway in the regulation of the gonocyte to pre-spermatogonia transition during human fetal testis development [19] and involvement in regulating pluripotency factor expression in fetal germ cells (reviewed in [20]). Furthermore, high expression of the Nodal signalling factors NODAL, LEFTY1 and CRIPTO has been reported in GCNIS cells, TGCTs and TGCTderived cell lines [12,16,17], and several studies have found co-expression of Nodal signalling and pluripotency factors in NTera2 cells [12,15].…”

Prenatal exposure to benzo[a]pyrene depletes ovarian reserve and masculinizes embryonic ovarian germ cell transcriptome transgenerationally

“…Among the male PGC genes with increased expression in female BaP-exposed E13.5 PGCs compared to vehicle controls were Tdgf1 , the co-receptor of NODAL binding to its Type 2 Activin receptor, and Lefty2 , whose expression is upregulated by NODAL signaling and which in turn inhibits NODAL signaling 44 . Both Tdgf1 and Lefty2 were in the top 25 DEGs when comparing female F1 2 mg/kg-day BaP (FDR P < 0.002), female F3 0.03 mg/kg-day BaP (FDR P < 0.04), and female F3 0.2 mg/kg-day BaP (FDR P < 0.001) to respective F1 and F3 controls, and Tdgf1 was the top DEG when comparing female F3 2.0 mg/kg-day BaP to F3 vehicle controls (FDR P = 0.017).…”

Sex-biased genetic regulation of inflammatory proteins in the Dutch population

“…Activin is mainly produced in the male reproductive tract and helps main cell–cell interactions, especially in the testis and prostate [ 38 ]. Similarly, the nodal signaling pathway is known to regulate fetal testicular development and uncontrolled nodal signaling has been implicated in testicular cancer [ 39 ]. While these downstream observations strongly support the validity of the identified sex-dependent pQTL variants, further mechanistic studies are required to discern the mechanisms by which these pathways drive sex-specific pQTLs.…”