Identification of a Novel Zebrafish Mutant Line that Develops Testicular Germ Cell Tumors.

Abstract

Testicular tumors are the most common solid malignant tumors in men 20-35 years of age. Although most of testicular tumors are curable, current treatments still fail in 15%-20% of patients. However, insufficient understanding of the molecular basis and lack of animal models limit development of more effective treatments. This study reports the identification of a novel zebrafish mutant line, ns1402, which develops testicular germ cell tumors (TGCTs). While both male and female ns1402 mutants were fertile at young age, male ns1402 mutants became infertile as early as 9 months of age. This infertility was associated with progressive loss of mature sperm. Failure of spermatogenesis was, at least in part, explained by progressive loss of mature Leydig cells, a source of testosterone that is essential for spermatogenesis. Interestingly, TGCTs in ns1402 mutants contained a large number of Sertoli cells and gene expression profiles of Sertoli cells were altered before loss of mature Leydig cells. This suggests that changes in Sertoli cell properties happened first, followed by loss of mature Leydig cells and failure of spermatogenesis. Taken together, this study emphasizes the importance of cell-cell interactions and cell signaling in the testis for spermatogenesis and tissue homeostasis.