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Development. 2016 Mar 1;143(5):787-98. doi: 10.1242/dev.128553. Epub 2016 Jan 25.

Tpbpa-Cre-mediated deletion of TFAP2C leads to deregulation of Cdkn1a, Akt1 and the ERK pathway, causing placental growth arrest.

Author information

1
Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, 53127 Bonn, Germany.
2
Institute of Molecular Biology, University of Duisburg-Essen, University Clinics, 45211 Essen, Germany.
3
Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
4
Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53105 Bonn, Germany.
5
Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, 53127 Bonn, Germany Hubert.Schorle@ukb.uni-bonn.de.

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 extra-embryonic 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.

KEYWORDS:

Junctional zone; MAPK; Placenta; TFAP2C; TPBPA; Trophoblast

PMID:
26811378
DOI:
10.1242/dev.128553
[Indexed for MEDLINE]
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