Reduced Gene Dosage of Tfap2c Impairs Trophoblast Lineage Differentiation and Alters Maternal Blood Spaces in the Mouse Placenta1

Abstract

Tfap2c is required for placental development and trophoblast stem cell maintenance. Deletion of Tfap2c results in early embryonic loss because of failure in placental development. We evaluated the effect of reduced Tfap2c expression on fetal outcome and placental development. Sixty percent of the heterozygous mice were lost directly after birth. Labyrinthine differentiation was impaired, as indicated by enhanced proliferation and inclusions of cobblestone-shaped cell clusters characterized by expression of Tfap2c and glycogen stores. Moreover, expression of marker genes such as Cdx2, Eomes, Gata3, and Ascl2 are decreased in the spongiotrophoblast and indicate a lowered stem cell potential. On Day 18.5 postcoitum, the labyrinth layer of Tfap2c(+/-) placentas exhibited massive hemorrhages in the maternal blood spaces; these hemorrhages might have contributed to the significantly reduced number of live-born pups. These morphological alterations were accompanied by a shift toward sinusoidal trophoblast giant cells as the cell subpopulation lining the maternal sinusoids and toward reduction in expression of the prolactin gene family member Prl2c2, a finding characteristic of the spiral arteries lining trophoblast cells. The trophoblast stem cells heterozygous for Tfap2c exhibited a reduction in the expression level of stem cell markers and in their proliferation and differentiation capacity but did not exhibit changes in marker genes of the trophoblast giant cell lineage. Taken together, these findings indicate that a reduction in the gene dosage of placental Tfap2c leads to morphological changes in the labyrinth at midgestation and in the maternal blood spaces during late pregnancy.

Single cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development

“…We identified a substantial fraction of transcriptional repressors ( IKZF5 , IFI16 , BHLME40 and CBFA2T2 ), genes associated with DNA mismatch repair ( PMS1 and MBD4 ), and several components of NFκβ ( BCL3 and RELA ) and WNT ( CDX1 , HBP1 and HMGN3 ) signalling pathways. Interestingly, the network also contained TFAP2C and GCM1 , which in mouse are associated with trophoblast lineage specification ( Kaiser et al, 2015 ; Sharma et al, 2016 ) and regulation of syncytium formation ( Kashif et al, 2011 ; Lu et al, 2016 ), respectively. For quantitative visualisation of species specificity, we plotted relative expression of transcription factors and epigenetic modifiers ( Fig.…”

Transcription factor ASCL2 is required for development of the glycogen trophoblast cell lineage

“…To develop a cell culture-based system for further analyses of this deletion, we established trophoblast stem cell (TSC) lines from blastocysts carrying a maternally or paternally inherited Del 7AI allele. Ascl2 levels peak between days 1 and 3 of TSC differentiation induced by FGF4 withdrawal [ 18 , 21 , 37 – 40 ]. Furthermore, RNA-seq profiling of hybrid TSC lines showed that Ascl2 is already imprinted in undifferentiated TSCs, with more than 90% of expression coming from the maternal allele [ 41 ].…”

Single-cell transcriptome analysis of human, marmoset and mouse embryos reveals common and divergent features of preimplantation development

“…We identified a substantial fraction of transcriptional repressors (IKZF5, IFI16, BHLME40 and CBFA2T2), genes associated with DNA mismatch repair (PMS1, MBD4) and several components of NFκβ (BCL3, RELA) and WNT (CDX1, HBP1, HMGN3) signalling pathways. Interestingly, the network also contained TFAP2C and GCM1, which in mouse are associated with trophoblast lineage specification (Kaiser et al, 2015;Sharma et al, 2016) and regulation of syncytium formation (Kashif et al, 2011;Lu et al, 2016), respectively. For quantitative visualisation of species specificity we plotted relative expression of transcription factors and epigenetic modifiers ( Fig.…”