title: Tpbpa-Cre-mediated deletion of TFAP2C leads to deregulation of Cdkn1a, Akt1 and the ERK pathway, causing 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 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.
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, 53127 Bonn, Germany.
authors.forename: Neha
authors.initials: N
authors.lastname: Sharma
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, 53127 Bonn, Germany.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kubaczka
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, University Clinics, 45211 Essen, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kaiser
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, 53127 Bonn, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Nettersheim
authors.affiliation: Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Sadaf S
authors.initials: SS
authors.lastname: Mughal
authors.affiliation: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Riesenberg
authors.affiliation: Unit for RNA Biology, Institute for Clinical Chemistry and Clinical Pharmacology, University Hospital Bonn, 53105 Bonn, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hölzel
authors.affiliation: Institute of Molecular Biology, University of Duisburg-Essen, University Clinics, 45211 Essen, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Winterhager
authors.affiliation: Department of Developmental Pathology, Institute of Pathology, University of Bonn Medical School, 53127 Bonn, Germany Hubert.Schorle@ukb.uni-bonn.de.
authors.forename: Hubert
authors.initials: H
authors.lastname: Schorle
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation; D003433:Crosses, Genetic; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000502:physiology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D006003:Glycogen / Q000378:metabolism; D017403:In Situ Hybridization; D019426:Integrases / Q000235:genetics / Q000502:physiology; D008297:Male; D051379:Mice; D010766:Phosphorylation; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011257:Pregnancy Proteins / Q000235:genetics / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D050656:Transcription Factor AP-2 / Q000235:genetics / Q000502:physiology*; D019076:Transgenes; D014327:Trophoblasts / Q000378:metabolism
chemical_list: C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D011257:Pregnancy Proteins; C583890:Tfap2c protein, mouse; C558404:Tpbpa protein, mouse; D050656:Transcription Factor AP-2; D006003:Glycogen; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; C045073:Cre recombinase; D019426:Integrases
keywords: Junctional zone; MAPK; Placenta; TFAP2C; TPBPA; Trophoblast