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

Joanie C. Neumann, Garvin L. Chandler, Vanessa A. Damoulis, Nicholas J. Fustinoa, Katherine Lillard, Leendert Looijenga, Linda Margraf, Dinesh Rakhejad, James F. Amatruda

Research output: Contribution to journalArticle

52 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)13153-13158
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number32
DOIs
StatePublished - Aug 9 2011

Keywords

  • Haplotype
  • Non-seminoma
  • SMAD
  • Teleost

ASJC Scopus subject areas

  • General

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    Neumann, J. C., Chandler, G. L., Damoulis, V. A., Fustinoa, N. J., Lillard, K., Looijenga, L., Margraf, L., Rakhejad, D., & 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), 13153-13158. https://doi.org/10.1073/pnas.1102311108