Critical function of AP-2 gamma/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 Prdm1 activity that is required for PGC maintenance, most likely mediating Prdm1-induced suppression of mesodermal differentiation.
Institute of Pathology, Department of Developmental Pathology, University of Bonn, Bonn, Germany.
Susanne
S
Weber
Dawid
D
Eckert
Daniel
D
Nettersheim
Ad J M
AJ
Gillis
Sabine
S
Schäfer
Peter
P
Kuckenberg
Julia
J
Ehlermann
Uwe
U
Werling
Katharina
K
Biermann
Leendert H J
LH
Looijenga
Hubert
H
Schorle
D000818:Animals; D017209:Apoptosis; D015415:Biomarkers / Q000378:metabolism; D005260:Female; D005854:Germ Cells / Q000254:growth & development* / Q000378:metabolism; D008297:Male; D008648:Mesoderm / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D000074462:Positive Regulatory Domain I-Binding Factor 1; D012098:Reproduction; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015854:Up-Regulation
D015415:Biomarkers; C513258:Prdm1 protein, mouse; C583890:Tfap2c protein, mouse; D050656:Transcription Factor AP-2; D014157:Transcription Factors; D000074462:Positive Regulatory Domain I-Binding Factor 1