Neumann, J.C., Chandler, G.L., Damoulis, V.A., Fustino, N.J., Lillard, K., Looijenga, L., Margraf, L., Rakheja, D., and Amatruda, J.F. (2011) Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish. Proceedings of the National Academy of Sciences of the United States of America. 108(32):13153-8.
Germ-cell tumors (GCTs), which arise from pluripotent embryonic germ cells, exhibit a wide range of histologic differentiation
states with varying clinical behaviors. 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. Alk6b is expressed in
spermatogonia and early oocytes, and alk6b mutant gonads display impaired BMP signal transduction, altered expression of BMP target genes, and abnormal germ-cell differentiation.
We find a similar absence of BMP signaling in undifferentiated human GCTs, such as seminomas and embryonal carcinoma, but
not in normal testis or in differentiated GCTs. These results indicate a germ-cell–autonomous role for BMP signal transduction
in germ-cell differentiation, and highlight the importance of the BMP pathway in human GCTs.
