The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency

Anthony D Krentz; Mark W Murphy; Shinseog Kim; Matthew S Cook; Blanche Capel; Rui Zhu; Angabin Matin; Aaron L Sarver; Keith L Parker; Michael D Griswold; Leendert H J Looijenga; Vivian J Bardwell; David Zarkower

doi:10.1073/pnas.0905431106

Back

The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency

Journal article

Open access

The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency

Anthony D Krentz, Mark W Murphy, Shinseog Kim, Matthew S Cook, Blanche Capel, Rui Zhu, Angabin Matin, Aaron L Sarver, Keith L Parker, Michael D Griswold, …

Proceedings of the National Academy of Sciences - PNAS, Vol.106(52), pp.22323-22328

12/29/2009

DOI: https://doi.org/10.1073/pnas.0905431106

Handle:

https://hdl.handle.net/2376/113502

PMCID: PMC2799724

PMID: 20007774

Files and links (1)

url

https://doi.org/10.1073/pnas.0905431106View

Published (Version of record) Open

Abstract

Proto-Oncogene Proteins c-ret - metabolism

Cell Proliferation

Fetal Stem Cells - cytology

Spermatogenesis - genetics

Fetal Stem Cells - metabolism

Humans

Male

Neoplasms, Germ Cell and Embryonal - genetics

Neoplasm Proteins - metabolism

Testicular Neoplasms - pathology

Teratoma - metabolism

Cell Differentiation

Neoplasm Proteins - genetics

Genes, Tumor Suppressor

PTEN Phosphohydrolase - genetics

Gene Expression

Testicular Neoplasms - genetics

Transcription Factors - physiology

Pluripotent Stem Cells - cytology

Mice, Inbred C57BL

Testicular Neoplasms - metabolism

PTEN Phosphohydrolase - metabolism

Neoplasms, Germ Cell and Embryonal - metabolism

Gene Dosage

Transcription Factors - genetics

Mice, Knockout

Pluripotent Stem Cells - metabolism

Phenotype

Spermatogenesis - physiology

Teratoma - pathology

Animals

Teratoma - genetics

Mice

Mutation

Neoplasms, Germ Cell and Embryonal - pathology

Proto-Oncogene Proteins c-ret - genetics

Dmrt1 (doublesex and mab-3 related transcription factor 1) is a conserved transcriptional regulator of male differentiation required for testicular development in vertebrates. Here, we show that in mice of the 129Sv strain, loss of Dmrt1 causes a high incidence of teratomas, whereas these tumors do not form in Dmrt1 mutant C57BL/6J mice. Conditional gene targeting indicates that Dmrt1 is required in fetal germ cells but not in Sertoli cells to prevent teratoma formation. Mutant 129Sv germ cells undergo apparently normal differentiation up to embryonic day 13.5 (E13.5), but some cells fail to arrest mitosis and ectopically express pluripotency markers. Expression analysis and chromatin immunoprecipitation identified DMRT1 target genes, whose missexpression may underlie teratoma formation. DMRT1 indirectly activates the GDNF coreceptor Ret, and it directly represses the pluripotency regulator Sox2. Analysis of human germ cell tumors reveals similar gene expression changes correlated to DMRT1 levels. Dmrt1 behaves genetically as a dose-sensitive tumor suppressor gene in 129Sv mice, and natural variation in Dmrt1 activity can confer teratoma susceptibility. This work reveals a genetic link between testicular dysgenesis, pluripotency regulation, and teratoma susceptibility that is highly sensitive to genetic background and to gene dosage.

Metrics

5 Record Views

Details

Title: The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency
Creators: Anthony D Krentz - Department of Genetics, Developmental Biology Center, and Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
Mark W Murphy
Shinseog Kim
Matthew S Cook
Blanche Capel
Rui Zhu
Angabin Matin
Aaron L Sarver
Keith L Parker
Michael D Griswold
Leendert H J Looijenga
Vivian J Bardwell
David Zarkower
Publication Details: Proceedings of the National Academy of Sciences - PNAS, Vol.106(52), pp.22323-22328
Academic Unit: Molecular Biosciences, School of
Publisher: United States
Grant note: R01 CA093754 / NCI NIH HHS T32 HD007480 / NICHD NIH HHS CA093754 / NCI NIH HHS R01 GM059152 / NIGMS NIH HHS GM59152 / NIGMS NIH HHS T32HD007480 / NICHD NIH HHS R01 GM087500 / NIGMS NIH HHS
Identifiers: 99900547973001842
Language: English
Resource Type: Journal article