The DM domain protein DMRT1 is a dose-sensitive regulator of fetal germ cell proliferation and pluripotency.
نویسندگان
چکیده
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.
منابع مشابه
Dev122184 1083..1088
Genes related to Dmrt1, which encodes a DNA-binding DM domain transcription factor, act as triggers for primary sex determination in a broad range of metazoan species. However, this role is fulfilled in mammalsbySry, anewlyevolvedgeneon theYchromosome, such that Dmrt1 has become dispensable for primary sex determination and instead maintains Sertoli cell phenotype in postnatal testes. Here, we ...
متن کاملI-51: The Role of the Transcription FactorGCNF in Germ Cell Differentiation and Reproductionin Mice
The germ cell nuclear factor (GCNF) is a member of the nuclear receptor super family of transcription factors. GCNF expression during gastrulation and neurulation is critical for normal embryogenesis in mice. GCNF represses expression of the POU domain transcription factor Oct4 during mouse post-implantation development in vivo. Oct4 is thus down-regulated during female gonadal development, whe...
متن کاملTranscription Factor TFAP2C Regulates Major Programs Required for Murine Fetal Germ Cell Maintenance and Haploinsufficiency Predisposes to Teratomas in Male Mice
Maintenance and maturation of primordial germ cells is controlled by complex genetic and epigenetic cascades, and disturbances in this network lead to either infertility or malignant aberration. Transcription factor TFAP2C has been described to be essential for primordial germ cell maintenance and to be upregulated in several human germ cell cancers. Using global gene expression profiling, we i...
متن کاملDMRT1 promotes oogenesis by transcriptional activation of Stra8 in the mammalian fetal ovary.
Dmrt1 belongs to the DM domain gene family of conserved sexual regulators. In the mouse Dmrt1 is expressed in the genital ridge (the gonadal primordium) in both sexes and then becomes testis-specific shortly after sex determination. The essential role of DMRT1 in testicular differentiation is well established, and includes transcriptional repression of the meiotic inducer Stra8. However Dmrt1 m...
متن کاملThe Role of Wnt/β-catenin Signaling Pathway in Rat Primordial Germ Cells Reprogramming and Induction into Pluripotent State
Primordial Germ Cells (PGCs) are unipotent precursors of the gametes. PGCs can give rise to a type of pluripotent stem cells in vitro that are called embryonic germ (EG) cells. PGCs can also acquire such pluripotency in vivo and generate teratomas. Under specific culture conditions, PGCs can be reprogrammed to embryonic germ cells which are capable of expression of key pluripotency marker...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید
ثبت ناماگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید
ورودعنوان ژورنال:
- Proceedings of the National Academy of Sciences of the United States of America
دوره 106 52 شماره
صفحات -
تاریخ انتشار 2009