title: Transcription factor AP-2γ induces early Cdx2 expression and represses HIPPO signaling to specify the trophectoderm lineage.
abstract: Cell fate decisions are fundamental to the development of multicellular organisms. In mammals the first cell fate decision involves segregation of the pluripotent inner cell mass and the trophectoderm, a process regulated by cell polarity proteins, HIPPO signaling and lineage-specific transcription factors such as CDX2. However, the regulatory mechanisms that operate upstream to specify the trophectoderm lineage have not been established. Here we report that transcription factor AP-2γ (TFAP2C) functions as a novel upstream regulator of Cdx2 expression and position-dependent HIPPO signaling in mice. Loss- and gain-of-function studies and promoter analysis revealed that TFAP2C binding to an intronic enhancer is required for activation of Cdx2 expression during early development. During the 8-cell to morula transition TFAP2C potentiates cell polarity to suppress HIPPO signaling in the outside blastomeres. TFAP2C depletion triggered downregulation of PARD6B, loss of apical cell polarity, disorganization of F-actin, and activation of HIPPO signaling in the outside blastomeres. Rescue experiments using Pard6b mRNA restored cell polarity but only partially corrected position-dependent HIPPO signaling, suggesting that TFAP2C negatively regulates HIPPO signaling via multiple pathways. Several genes involved in regulation of the actin cytoskeleton (including Rock1, Rock2) were downregulated in TFAP2C-depleted embryos. Inhibition of ROCK1 and ROCK2 activity during the 8-cell to morula transition phenocopied TFAP2C knockdown, triggering a loss of position-dependent HIPPO signaling and decrease in Cdx2 expression. Altogether, these results demonstrate that TFAP2C facilitates trophectoderm lineage specification by functioning as a key regulator of Cdx2 transcription, cell polarity and position-dependent HIPPO signaling.
authors: Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA.
authors: Zubing
authors: Z
authors: Cao
authors: Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA.
authors: Timothy S
authors: TS
authors: Carey
authors: Department of Pathology and Laboratory Medicine, Institute of Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Avishek
authors: A
authors: Ganguly
authors: Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA.
authors: Catherine A
authors: CA
authors: Wilson
authors: Department of Pathology and Laboratory Medicine, Institute of Reproductive Health and Regenerative Medicine, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors: Soumen
authors: S
authors: Paul
authors: Developmental Epigenetics Laboratory, Department of Animal Science, Michigan State University, East Lansing, MI 48824, USA knottj@msu.edu.
authors: Jason G
authors: JG
authors: Knott
mesh_terms: D000577:Amides / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000071616:CDX2 Transcription Factor; D002454:Cell Differentiation / Q000502:physiology*; D019070:Cell Lineage / Q000502:physiology*; D016764:Cell Polarity / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D000090683:Hippo Signaling Pathway; D018398:Homeodomain Proteins / Q000378:metabolism*; D008156:Luciferases; D051379:Mice; D008856:Microscopy, Fluorescence; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D050656:Transcription Factor AP-2 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism*; D014327:Trophoblasts / Q000502:physiology*; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D000577:Amides; D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D011725:Pyridines; D034741:RNA, Small Interfering; D050656:Transcription Factor AP-2; D014157:Transcription Factors; C108830:Y 27632; D008156:Luciferases; D017346:Protein Serine-Threonine Kinases; C515854:Rock1 protein, mouse; C515855:Rock2 protein, mouse; D054460:rho-Associated Kinases
keywords: CDX2; Cell polarity; HIPPO signaling; Mouse; TFAP2C