title: Transcription factor TFAP2C regulates major programs required for murine fetal germ cell maintenance and haploinsufficiency predisposes to teratomas in male mice.
abstract: 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.
authors: University of Bonn Medical School, Institute of Pathology, Department of Developmental Pathology, Bonn, Germany.
authors: Jana
authors: J
authors: Schemmer
authors: Marcos J
authors: MJ
authors: Araúzo-Bravo
authors: Natalie
authors: N
authors: Haas
authors: Sabine
authors: S
authors: Schäfer
authors: Susanne N
authors: SN
authors: Weber
authors: Astrid
authors: A
authors: Becker
authors: Dawid
authors: D
authors: Eckert
authors: Andreas
authors: A
authors: Zimmer
authors: Daniel
authors: D
authors: Nettersheim
authors: Hubert
authors: H
authors: Schorle
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D016000:Cluster Analysis; D053595:Embryonic Stem Cells; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease; D005854:Germ Cells / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D057895:Haploinsufficiency; D006579:Heterozygote; D000090062:Kruppel-Like Factor 4; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D013724:Teratoma / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D050656:Transcription Factor AP-2 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; C477342:Nanos3 protein, mouse; D016601:RNA-Binding Proteins; C583890:Tfap2c protein, mouse; D050656:Transcription Factor AP-2
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