Transcription factor AP-2γ is a core regulator of tight junction biogenesis and cavity formation during mouse early embryogenesis

The trophectoderm epithelium is the first differentiated cell layer to arise during mammalian development. Blastocyst formation requires the proper expression and localization of tight junction, polarity, ion gradient and H2O channel proteins in the outer cell membranes. However, the underlying transcriptional mechanisms that control their expression are largely unknown. Here, we report that transcription factor AP-2γ (Tcfap2c) is a core regulator of blastocyst formation in mice. Bioinformatics, chromatin immunoprecipitation and transcriptional analysis revealed that Tcfap2c binds and regulates a diverse group of genes expressed during blastocyst formation. RNA interference experiments demonstrated that Tcfap2c regulates genes important for tight junctions, cell polarity and fluid accumulation. Functional and ultrastructural studies revealed that Tcfap2c is necessary for tight junction assembly and paracellular sealing in trophectoderm epithelium. Aggregation of control eight-cell embryos with Tcfap2c knockdown embryos rescued blastocyst formation via direct contribution to the trophectoderm epithelium. Finally, we found that Tcfap2c promotes cellular proliferation via direct repression of p21 transcription during the morula-to-blastocyst transition. We propose a model in which Tcfap2c acts in a hierarchy to facilitate blastocyst formation through transcriptional regulation of core genes involved in tight junction assembly, fluid accumulation and cellular proliferation.

[1]  M. Calder,et al.  Ouabain Stimulates a Na+/K+-ATPase-Mediated SFK-Activated Signalling Pathway That Regulates Tight Junction Function in the Mouse Blastocyst , 2011, PloS one.

[2]  S. Kimber,et al.  Sox2 Is Essential for Formation of Trophectoderm in the Preimplantation Embryo , 2010, PloS one.

[3]  V. Alarcon Cell Polarity Regulator PARD6B Is Essential for Trophectoderm Formation in the Preimplantation Mouse Embryo1 , 2010, Biology of reproduction.

[4]  M. Zernicka-Goetz,et al.  Epigenetic Modification Affecting Expression of Cell Polarity and Cell Fate Genes to Regulate Lineage Specification in the Early Mouse Embryo , 2010, Molecular biology of the cell.

[5]  L. Magnani,et al.  Brg1 Is Required for Cdx2-Mediated Repression of Oct4 Expression in Mouse Blastocysts , 2010, PloS one.

[6]  Hubert Schorle,et al.  The Transcription Factor TCFAP2C/AP-2γ Cooperates with CDX2 To Maintain Trophectoderm Formation , 2010, Molecular and Cellular Biology.

[7]  J. Rossant,et al.  Making the blastocyst: lessons from the mouse. , 2010, The Journal of clinical investigation.

[8]  Benjamin L. Kidder,et al.  Examination of transcriptional networks reveals an important role for TCFAP2C, SMARCA4, and EOMES in trophoblast stem cell maintenance. , 2010, Genome research.

[9]  J. Rossant,et al.  Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2 , 2010, Development.

[10]  D. Tesfaye,et al.  Suppression of keratin 18 gene expression in bovine blastocysts by RNA interference. , 2010, Reproduction, fertility, and development.

[11]  Julia Tischler,et al.  The Cyclin-Dependent Kinase Inhibitor p21 Is a Crucial Target for Histone Deacetylase 1 as a Regulator of Cellular Proliferation , 2009, Molecular and Cellular Biology.

[12]  Christopher Williams,et al.  AP‐2γ promotes proliferation in breast tumour cells by direct repression of the CDKN1A gene , 2009, The EMBO journal.

[13]  E. McSherry,et al.  Tight Junctions: A Barrier to the Initiation and Progression of Breast Cancer? , 2009, Journal of biomedicine & biotechnology.

[14]  Geppino Falco,et al.  Uncovering early response of gene regulatory networks in ESCs by systematic induction of transcription factors. , 2009, Cell stem cell.

[15]  Soumen Paul,et al.  GATA3 Is Selectively Expressed in the Trophectoderm of Peri-implantation Embryo and Directly Regulates Cdx2 Gene Expression* , 2009, The Journal of Biological Chemistry.

[16]  Benjamin L. Kidder,et al.  SWI/SNF‐Brg1 Regulates Self‐Renewal and Occupies Core Pluripotency‐Related Genes in Embryonic Stem Cells , 2009, Stem cells.

[17]  T. Papenbrock,et al.  Tight junction protein ZO-2 expression and relative function of ZO-1 and ZO-2 during mouse blastocyst formation. , 2008, Experimental cell research.

[18]  W. Reik,et al.  Epigenetic restriction of embryonic cell lineage fate by methylation of Elf5 , 2008, Nature Cell Biology.

[19]  R. Schultz,et al.  Histone deacetylase 1 (HDAC1) regulates histone acetylation, development, and gene expression in preimplantation mouse embryos. , 2008, Developmental biology.

[20]  S. Hahn Transcriptional regulation , 2008, EMBO reports.

[21]  T. Noda,et al.  Deficiency of zonula occludens-1 causes embryonic lethal phenotype associated with defected yolk sac angiogenesis and apoptosis of embryonic cells. , 2008, Molecular biology of the cell.

[22]  Shinji Yamamoto,et al.  Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos , 2008, Mechanisms of Development.

[23]  J. Eckert,et al.  Tight junction biogenesis during early development. , 2008, Biochimica et biophysica acta.

[24]  J. Piontek,et al.  Structure and function of claudins. , 2008, Biochimica et biophysica acta.

[25]  P. J. Kausalya,et al.  Early Embryonic Lethality of Mice Lacking ZO-2, but Not ZO-3, Reveals Critical and Nonredundant Roles for Individual Zonula Occludens Proteins in Mammalian Development , 2008, Molecular and Cellular Biology.

[26]  Shoichiro Tsukita,et al.  Tight junctions containing claudin 4 and 6 are essential for blastocyst formation in preimplantation mouse embryos. , 2007, Developmental biology.

[27]  Takashi Hiiragi,et al.  Stochastic patterning in the mouse pre-implantation embryo , 2007, Development.

[28]  M. DePamphilis,et al.  Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development , 2007, Development.

[29]  O. Niwa,et al.  p21 provides stage specific DNA damage control to preimplantation embryos , 2007, Oncogene.

[30]  P. Madan,et al.  Na/K-ATPase β1 Subunit Expression Is Required for Blastocyst Formation and Normal Assembly of Trophectoderm Tight Junction-associated Proteins* , 2007, Journal of Biological Chemistry.

[31]  Jian Huang,et al.  Analysis of Transcription Factor AP-2 Expression and Function During Mouse Preimplantation Development1 , 2006, Biology of reproduction.

[32]  R. Jäger,et al.  The AP-2 family of transcription factors , 2005, Genome Biology.

[33]  Janet Rossant,et al.  Interaction between Oct3/4 and Cdx2 Determines Trophectoderm Differentiation , 2005, Cell.

[34]  Ralf Herwig,et al.  Primary Differentiation in the Human Blastocyst: Comparative Molecular Portraits of Inner Cell Mass and Trophectoderm Cells , 2005, Stem cells.

[35]  Janet Rossant,et al.  Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst , 2005, Development.

[36]  B. Margolis,et al.  PATJ regulates tight junction formation and polarity in mammalian epithelial cells , 2005, The Journal of cell biology.

[37]  E. Dejana,et al.  Contribution of JAM-1 to epithelial differentiation and tight-junction biogenesis in the mouse preimplantation embryo , 2004, Journal of Cell Science.

[38]  Wilhelmine N. de Vries,et al.  Maternal β-catenin and E-cadherin in mouse development , 2004 .

[39]  K. Tasaka,et al.  Rho-kinase is involved in mouse blastocyst cavity formation. , 2004, Biochemical and biophysical research communications.

[40]  R. D. Lynch,et al.  The tight junction: a multifunctional complex. , 2004, American journal of physiology. Cell physiology.

[41]  J. Lingrel,et al.  Deletion of the Na/K-ATPase α1-subunit gene (Atp1a1) does not prevent cavitation of the preimplantation mouse embryo , 2004, Mechanisms of Development.

[42]  M. Gye,et al.  Role of occludin, a tight junction protein, in blastocoel formation, and in the paracellular permeability and differentiation of trophectoderm in preimplantation mouse embryos. , 2004, Molecules and cells.

[43]  David K Gardner,et al.  Single blastocyst transfer: a prospective randomized trial. , 2004, Fertility and sterility.

[44]  S. Butz,et al.  The junctional adhesion molecule (JAM) family members JAM-2 and JAM-3 associate with the cell polarity protein PAR-3: a possible role for JAMs in endothelial cell polarity , 2003, Journal of Cell Science.

[45]  M. Murakami,et al.  The Homeoprotein Nanog Is Required for Maintenance of Pluripotency in Mouse Epiblast and ES Cells , 2003, Cell.

[46]  P. Thomsen,et al.  Aquaporin proteins in murine trophectoderm mediate transepithelial water movements during cavitation. , 2003, Developmental biology.

[47]  O. Bachs,et al.  Increased expression of the cyclin-dependent kinase inhibitor p27 in cleavage-stage human embryos exhibiting developmental arrest. , 2002, Molecular human reproduction.

[48]  T. Nottoli,et al.  Transcription factor AP-2gamma is essential in the extra-embryonic lineages for early postimplantation development. , 2002, Development.

[49]  A. J. Watson,et al.  Regulation of blastocyst formation. , 2001, Frontiers in bioscience : a journal and virtual library.

[50]  T. Noda,et al.  Complex phenotype of mice lacking occludin, a component of tight junction strands. , 2000, Molecular biology of the cell.

[51]  S. Aparício,et al.  Eomesodermin is required for mouse trophoblast development and mesoderm formation , 2000, Nature.

[52]  James M. Roberts,et al.  CDK inhibitors: positive and negative regulators of G1-phase progression. , 1999, Genes & development.

[53]  A. Gartel,et al.  Transcriptional regulation of the p21((WAF1/CIP1)) gene. , 1999, Experimental cell research.

[54]  H. Schöler,et al.  Formation of Pluripotent Stem Cells in the Mammalian Embryo Depends on the POU Transcription Factor Oct4 , 1998, Cell.

[55]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[56]  D. Riethmacher,et al.  A targeted mutation in the mouse E-cadherin gene results in defective preimplantation development. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[57]  L. Larue,et al.  E-cadherin null mutant embryos fail to form a trophectoderm epithelium. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[58]  A. Copp Interaction between inner cell mass and trophectoderm of the mouse blastocyst. II. The fate of the polar trophectoderm. , 1979, Journal of embryology and experimental morphology.

[59]  A. Copp Interaction between inner cell mass and trophectoderm of the mouse blastocyst. I. A study of cellular proliferation. , 1978, Journal of embryology and experimental morphology.

[60]  C. Farquhar,et al.  Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology. , 2012, The Cochrane database of systematic reviews.

[61]  A. Evsikov,et al.  Maternal beta-catenin and E-cadherin in mouse development. , 2004, Development.

[62]  J. Vandesompele,et al.  Bmc Developmental Biology Identification and Expression Analysis of Genes Associated with Bovine Blastocyst Formation , 2022 .