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PMID:21775673

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Citation

Neumann, JC, Chandler, GL, Damoulis, VA, Fustino, NJ, Lillard, K, Looijenga, L, Margraf, L, Rakheja, D and Amatruda, JF (2011) Mutation in the type IB bone morphogenetic protein receptor Alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish. Proc. Natl. Acad. Sci. U.S.A. 108:13153-8

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.

Links

PubMed PMC3156187 Online version:10.1073/pnas.1102311108

Keywords

Alleles; Animals; Base Sequence; Bone Morphogenetic Protein Receptors, Type I/genetics; Bone Morphogenetic Protein Receptors, Type I/metabolism; Cell Differentiation/genetics; Cloning, Molecular; Female; Genetic Loci/genetics; Germ Cells/metabolism; Germ Cells/pathology; Humans; Male; Meiosis; Molecular Sequence Data; Mutation/genetics; Neoplasms, Germ Cell and Embryonal/genetics; Neoplasms, Germ Cell and Embryonal/pathology; Ovary/metabolism; Ovary/pathology; Signal Transduction; Spermatozoa/metabolism; Spermatozoa/pathology; Testicular Neoplasms/genetics; Testicular Neoplasms/pathology; Testis/metabolism; Testis/pathology; Zebrafish/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

DANRE:A0A0R4I9Y4

involved_in

GO:0030509: BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-111220-2

P

Seeded From UniProt

complete

DANRE:A0A0R4I9Y4

involved_in

GO:0042078: germ-line stem cell division

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-111220-2

P

Seeded From UniProt

complete

DANRE:A8WG63

involved_in

GO:0030509: BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-111220-2

P

Seeded From UniProt

complete

DANRE:A8WG63

involved_in

GO:0042078: germ-line stem cell division

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-111220-2

P

Seeded From UniProt

complete

DANRE:C0L3D6

involved_in

GO:0030509: BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-111220-2

P

Seeded From UniProt

complete

DANRE:C0L3D6

involved_in

GO:0042078: germ-line stem cell division

ECO:0000315: mutant phenotype evidence used in manual assertion

ZFIN:ZDB-GENO-111220-2

P

Seeded From UniProt

complete


See also

References

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