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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 identified genes deregulated upon loss of  Tfap2c  in embryonic stem cells and primordial germ cell-like cells. We show that loss of  Tfap2c  affects many aspects of the genetic network regulating germ cell biology, such as downregulation of maturation markers and induction of markers indicative for somatic differentiation, cell cycle, epigenetic remodeling and pluripotency. Chromatin-immunoprecipitation analyses demonstrated binding of TFAP2C to regulatory regions of deregulated genes ( Sfrp1, Dmrt1 ,  Nanos3 ,  c-Kit ,  Cdk6 ,  Cdkn1a ,  Fgf4 ,  Klf4 ,  Dnmt3b  and  Dnmt3l ) suggesting that these genes are direct transcriptional targets of TFAP2C in primordial germ cells. Since  Tfap2c  deficient primordial germ cell-like cells display cancer related deregulations in epigenetic remodeling, cell cycle and pluripotency control, the  Tfap2c -knockout allele was bred onto 129S2/Sv genetic background. There, mice heterozygous for  Tfap2c  develop with high incidence germ cell cancer resembling human pediatric germ cell tumors. Precursor lesions can be observed as early as E16.5 in developing testes displaying persisting expression of pluripotency markers. We further demonstrate that mice with a heterozygous deletion of the TFAP2C target gene  Nanos3  are also prone to develop teratomas. These data highlight TFAP2C as a critical and dose-sensitive regulator of germ cell fate.

plos one

Transcription Factor TFAP2C Regulates Major Programs Required for Murine Fetal Germ Cell Maintenance and Haploinsufficiency Predisposes to Teratomas in Male Mice