Critical function of AP-2gamma/TCFAP2C in mouse embryonic germ cell maintenance
Formation of the germ cell lineage involves multiple processes, including repression of somatic differentiation and reacquisition of pluripotency as well as a unique epigenetic constitution. The transcriptional regulator Prdm1 has been identified as a main coordinator of this process, controlling epigenetic modification and gene expression. Here we report on the expression pattern of the transcription factor Tcfap2c, a putative downstream target of Prdm1, during normal mouse embryogenesis and the consequences of its specific loss in primordial germ cells (PGCs) and their derivatives. Tcfap2c is expressed in PGCs from Embryonic Day 7.25 (E 7.25) up to E 12.5, and targeted disruption resulted in sterile animals, both male and female. In the mutant animals, PGCs were specified but were lost around E 8.0. PGCs generated in vitro from embryonic stem cells lacking TCFAP2C displayed induction of Prdm1 and Dppa3. Upregulation of Hoxa1, Hoxb1, and T together with lack of expression of germ cell markers such Nanos3, Dazl, and Mutyh suggested that the somatic gene program is induced in TCFAP2C-deficient PGCs. Repression of TCFAP2C in TCam-2, a human PGC-resembling seminoma cell line, resulted in specific upregulation of HOXA1, HOXB1, MYOD1, and HAND1, indicative of mesodermal differentiation. Expression of genes indicative of ectodermal, endodermal, or extraembryonic differentiation, as well as the finding of no change to epigenetic modifications, suggested control by other factors. Our results implicate Tcfap2c as an important effector of Prdml activity that is required for PGC maintenance, most likely mediating Prdm1-induced suppression of mesodermal differentiation.
|Keywords||AP-2γ, B lymphocyte induced maturation protein 1, DNA glycosylase MutY, Dazl protein, Developmental biology, Gamete biology, Gene regulation, HOXB1, MyoD1 protein, Nanos 3 protein, PRDM1, Prdm1 protein, Primordial germ cells, Somatic differentiation, TCFAP2C, TCam-2, Tcfap2c protein, aminomethyltransferase, animal, animal experiment, animal tissue, apoptosis, article, binding protein, biological marker, cell differentiation, controlled study, development and aging, dipeptide binding protein, embryo, embryo cell, embryo development, female, gene expression regulation, germ cell, growth, homeobox B1 protein, in vitro study, male, membrane protein, mesoderm, metabolism, mouse, mutant, nonhuman, primordial germ cell, priority journal, protein function, reproduction, transcription factor, transcription factor AP 2, transcription factor HAND 1, transcription factor HOXA 1, transcription factor TCFAP2C, transgenic mouse, unclassified drug, upregulation|
|Persistent URL||dx.doi.org/10.1095/biolreprod.109.078717, hdl.handle.net/1765/19931|
Weber, S., Eckert, D., Nettersheim, D., Gillis, A.J.M., Schäfer, S., Kuckenberg, P., … Schorle, H.. (2010). Critical function of AP-2gamma/TCFAP2C in mouse embryonic germ cell maintenance. Biology of Reproduction, 82(1), 214–223. doi:10.1095/biolreprod.109.078717