Critical Function of AP-2gamma/TCFAP2C in Mouse Embryonic Germ Cell Maintenance1

Abstract

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 Prdm1 activity that is required for PGC maintenance, most likely mediating Prdm1-induced suppression of mesodermal differentiation.

Essential Role of Sox2 for the Establishment and Maintenance of the Germ Cell Line

“…Up-to-date few genes have been demonstrated to be essential for the establishment of the germ cell line: Blimp1 [12], Prdm14 [16], Oct4 [18] and AP2-c [57]. Our present data show for the first time that also Sox2, at least in mice, is required for PGC development, both during their specification period and during their proliferative phase which precedes their sexual differentiation, through the regulation of genes which control their proliferation, their cellular identity as well as their potential pluripotency.…”

Primordial Germ Cells in Mice

“…The Yamaji et al 2008). Dotted arrows and dotted lines with terminal bars indicate genetic pathways for activation and for repression, respectively, as proposed based on in vitro experiments (Covello et al 2006;West et al 2009;Weber et al 2010). …”

“…It shows maternal expression in all cells until the blastocyst stage, but its expression is restricted in ExE and PGCs from E6.75 up to E12.5-E13.5 (Auman et al 2002;Werling and Schorle 2002;Weber et al 2010). Epiblast-specific deletion of Tcfap2c results in the drastically reduced PGCs, which show little migration and are lost later (Table 1) (Weber et al 2010). TCFAP2C may function downstream from BLIMP1 in PGCs (Fig.…”

“…BLIMP1 and PRDM14 are evolutionarily conserved proteins. Together with Tcfap2c (also known as AP2g) (Weber et al 2010), these genes are found to be required for PGC specification in mammals.…”

AP2γ regulates neural and epidermal development downstream of the BMP pathway at early stages of ectodermal patterning

“…AP2α also regulates neural border specification during the neuralization stage in Xenopus and lamprey [30,31]. Mouse AP2γ is expressed in both extraembryonic and embryonic tissues [32,33] and displays multiple functions in extraembryonic development, neural crest induction and terminal epidermal differentiation [26,34,35]. Moreover, disruption of AP2γ leads to mouse embryonic lethality at approximately E7.…”