Identification of a Heritable Model of Testicular Germ Cell Tumor in the Zebrafish

Abstract

Germ cell tumors (GCTs) affect infants, children and adults and are the most common cancer type in young men. Progress in understanding the molecular basis of germ cell tumors has been hampered by a lack of suitable animal models. Here we report the identification of a zebrafish model of highly penetrant, heritable testicular germ cell tumor isolated as part of a forward-genetic screen for cancer-susceptibility genes. The mutant line develops spontaneous testicular tumors at a median age of 7 months, and pedigree analysis indicates dominant inheritance of the germ cell tumor susceptibility trait. The zebrafish model exhibits disruption of testicular tissue architecture and the accumulation of primitive, spermatogonial-like cells with loss of spermatocytic differentiation. Radiation treatment leads to apoptosis of the tumor cells and tumor regression. The germ cell tumor-susceptible line can serve as a model for understanding the mechanisms regulating germ cells in normal development and disease, and as a platform investigating new therapeutic approaches for germ cell tumors.

Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish

“…Previously, we described the identification of a zebrafish model of heritable testicular GCT during a forward genetic screen to identify cancer susceptibility genes (17). Adult homozygous and heterozygous males from the testicular germ-cell tumor (tgct) mutant line develop gonadal tumors consisting of large, primitive germ cells (Fig.…”

“…However, the multiplicity of ligands, receptors, and cell types involved has made elucidation of specific signaling events difficult. We previously described a zebrafish mutant that develops highly penetrant, dominantly inherited testicular GCTs (tgct) (17). Here we report that a mutation in activin receptor-like kinase 6b (alk6b), the zebrafish homolog to human Bmpr1b, is responsible for the TGCT phenotype.…”

“…Although testicular GCT is the most common cancer of young men, the genes controlling the development and differentiation of GCTs remain largely unknown. Through a forward genetic screen, we previously identified a zebrafish mutant line, tgct, which develops spontaneous GCTs consisting of undifferentiated germ cells [Neumann JC, et al (2009) Zebrafish 6:319-327]. Using positional cloning we have identified an inactivating mutation in alk6b, a type IB bone morphogenetic protein (BMP) receptor, as the cause of the zebrafish GCT phenotype.…”

Hooked on zebrafish: insights into development and cancer of endocrine tissues

“…Several labs have performed screens in zebrafish to uncover cancer-related genes. Work from the Zon lab utilized phosphorylated histone H3 staining, a marker of proliferation, in a cell cycle screen to identify cancer prone mutants (Shepard et al 2005, Neumann et al 2009). These studies identified a zebrafish mutant of separase (also known as espl1, extra spindle poles like 1), an anaphase promoting cysteine protease (Shepard et al 2007).…”

“…These mutant zebrafish exhibited genome instability and increased cancer susceptibility. The cell cycle screen also identified a zebrafish model of germ cell tumors (Neumann et al 2009). Zebrafish harboring a mutation in laminin, g 1 (lamc1) exhibited, both spontaneous and carcinogen-induced, germ cell tumors.…”