Tpbpa mediated deletion of Tfap2c leads to deregulation of MAPK, P21, AKT and subsequent placental growth arrest

Abstract

Loss of TFAP2C in mouse leads to developmental defects in the extra-embryonic compartment with lethality at embryonic day (E)7.5. To investigate the requirement of TFAP2C in later placental development, deletion of TFAP2C was induced throughout extraembryonic ectoderm at E6.5, leading to severe placental abnormalities caused by reduced trophoblast population and resulting in embryonic retardation by E8.5. Deletion of TFAP2C in TPBPA + progenitors at E8.5 results in growth arrest of the junctional zone. TFAP2C regulates its target genes Cdkn1a ( previously p21) and Dusp6, which are involved in repression of MAPK signaling. Loss of TFAP2C reduces activation of ERK1/2 in the placenta. Downregulation of Akt1 and reduced activation of phosphorylated AKT in the mutant placenta are accompanied by impaired glycogen synthesis. Loss of TFAP2C led to upregulation of imprinted gene H19 and downregulation of Slc38a4 and Ascl2. The placental insufficiency post E16.5 causes fetal growth restriction, with 19% lighter mutant pups. Knockdown of TFAP2C in human trophoblast choriocarcinoma JAr cells inhibited MAPK and AKT signaling. Thus, we present a model where TFAP2C in trophoblasts controls proliferation by repressing Cdkn1a and activating the MAPK pathway, further supporting differentiation of glycogen cells by activating the AKT pathway.

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.…”

Placental insufficiency contributes to fatty acid metabolism alterations in aged female mouse offspring

“…Recently, we developed a genetic mouse model of placental insufficiency via growth arrest of the junctional zone of the placenta (45). This was accomplished by conditional ablation of transcription factor Tfap2c (transcription factor AP-2y) in Tpbpa-positive (trophoblast specific protein a) cell lineage at gestational day 14.5.…”

Mapping the chromatin landscape and Blimp1 transcriptional targets that regulate trophoblast differentiation

“…2E). For example, as shown in Figs 2F and 3A, d2 DARs are located proximal to a previously described regulator of trophoblast cell migration Ovol2 26 , Tfap2c known to govern trophoblast differentiation and proliferation 27–29 , and Prdm1 required for SpA-TGC specification 19 . These observations strongly suggest that increased accessibility promotes activation of proximal gene expression.…”

“…As for transfected P19 embryonal carcinoma cells 33 , here we observe occupancy by Blimp1 and Tfap2c at common target sites in trophoblasts, though it is not clear whether they bind independently or cooperatively in this case. Tfap2c functions as a transcriptional repressor governing trophoblast differentiation within the SpT layer 29 , but a cooperative Blimp1 and Tfap2c functional relationship has not previously been reported during placenta development. Interestingly, coexpression was recently confirmed in trophoblasts at the single-cell level 20 .…”