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

48 Citations (Scopus)

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

Fingerprint

Type I Bone Morphogenetic Protein Receptors
Germ Cell and Embryonal Neoplasms
Zebrafish
Germ Cells
Bone Morphogenetic Proteins
Cell Differentiation
Mutation
Signal Transduction
Embryonal Carcinoma
Seminoma
Spermatogonia
Gonads
Genes
Oocytes
Testis
Organism Cloning
Phenotype

Keywords

  • Haplotype
  • Non-seminoma
  • SMAD
  • Teleost

ASJC Scopus subject areas

  • General

Cite this

Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish. / Neumann, Joanie C.; Chandler, Garvin L.; Damoulis, Vanessa A.; Fustinoa, Nicholas J.; Lillard, Katherine; Looijenga, Leendert; Margraf, Linda; Rakhejad, Dinesh; Amatruda, James F.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 108, No. 32, 09.08.2011, p. 13153-13158.

Research output: Contribution to journalArticle

Neumann, Joanie C. ; Chandler, Garvin L. ; Damoulis, Vanessa A. ; Fustinoa, Nicholas J. ; Lillard, Katherine ; Looijenga, Leendert ; Margraf, Linda ; Rakhejad, Dinesh ; Amatruda, James F. / Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish. In: Proceedings of the National Academy of Sciences of the United States of America. 2011 ; Vol. 108, No. 32. pp. 13153-13158.
@article{0371609e9bb34631a7b7a6709ae9d4bc,
title = "Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish",
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.",
keywords = "Haplotype, Non-seminoma, SMAD, Teleost",
author = "Neumann, {Joanie C.} and Chandler, {Garvin L.} and Damoulis, {Vanessa A.} and Fustinoa, {Nicholas J.} and Katherine Lillard and Leendert Looijenga and Linda Margraf and Dinesh Rakhejad and Amatruda, {James F.}",
year = "2011",
month = "8",
day = "9",
doi = "10.1073/pnas.1102311108",
language = "English (US)",
volume = "108",
pages = "13153--13158",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "32",

}

TY - JOUR

T1 - Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish

AU - Neumann, Joanie C.

AU - Chandler, Garvin L.

AU - Damoulis, Vanessa A.

AU - Fustinoa, Nicholas J.

AU - Lillard, Katherine

AU - Looijenga, Leendert

AU - Margraf, Linda

AU - Rakhejad, Dinesh

AU - Amatruda, James F.

PY - 2011/8/9

Y1 - 2011/8/9

N2 - 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.

AB - 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.

KW - Haplotype

KW - Non-seminoma

KW - SMAD

KW - Teleost

UR - http://www.scopus.com/inward/record.url?scp=80052007885&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80052007885&partnerID=8YFLogxK

U2 - 10.1073/pnas.1102311108

DO - 10.1073/pnas.1102311108

M3 - Article

C2 - 21775673

AN - SCOPUS:80052007885

VL - 108

SP - 13153

EP - 13158

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 32

ER -