The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass.

Outside cells of the preimplantation mouse embryo form the trophectoderm (TE), a process requiring the transcription factor Tead4. Here, we show that transcriptionally active Tead4 can induce Cdx2 and other trophoblast genes in parallel in embryonic stem cells. In embryos, the Tead4 coactivator protein Yap localizes to nuclei of outside cells, and modulation of Tead4 or Yap activity leads to changes in Cdx2 expression. In inside cells, Yap is phosphorylated and cytoplasmic, and this involves the Hippo signaling pathway component Lats. We propose that active Tead4 promotes TE development in outside cells, whereas Tead4 activity is suppressed in inside cells by cell contact- and Lats-mediated inhibition of nuclear Yap localization. Thus, differential signaling between inside and outside cell populations leads to changes in cell fate specification during TE formation.

[1]  Scott Barolo,et al.  Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling. , 2002, Genes & development.

[2]  H. Kiyonari,et al.  Ssdp1 regulates head morphogenesis of mouse embryos by activating the Lim1-Ldb1 complex , 2005, Development.

[3]  B. Wang,et al.  The TEAD/TEF family of transcription factor Scalloped mediates Hippo signaling in organ size control. , 2008, Developmental cell.

[4]  H. Aburatani,et al.  Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ. , 2008, American journal of physiology. Renal physiology.

[5]  T. Magnuson,et al.  Defects in Yolk Sac Vasculogenesis, Chorioallantoic Fusion, and Embryonic Axis Elongation in Mice with Targeted Disruption of Yap65 , 2006, Molecular and Cellular Biology.

[6]  P. J. Welch,et al.  Differentiation of Mouse Embryonic Stem Cells after RNA Interference‐Mediated Silencing of OCT4 and Nanog , 2006, Stem cells.

[7]  Jianbin Huang,et al.  The Hippo Signaling Pathway Coordinately Regulates Cell Proliferation and Apoptosis by Inactivating Yorkie, the Drosophila Homolog of YAP , 2005, Cell.

[8]  B. Bruneau,et al.  Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity , 2004, The EMBO journal.

[9]  H. Kiyonari,et al.  Redundant Roles of Tead1 and Tead2 in Notochord Development and the Regulation of Cell Proliferation and Survival , 2008, Molecular and Cellular Biology.

[10]  G. Daley,et al.  Ras-MAPK signaling promotes trophectoderm formation from embryonic stem cells and mouse embryos , 2008, Nature Genetics.

[11]  Ryan S. Udan,et al.  The Fat Cadherin Acts through the Hippo Tumor-Suppressor Pathway to Regulate Tissue Size , 2006, Current Biology.

[12]  M. Ikawa,et al.  Lats2 Is an Essential Mitotic Regulator Required for the Coordination of Cell Division* , 2007, Journal of Biological Chemistry.

[13]  B. Edgar,et al.  Filling out the Hippo pathway , 2007, Nature Reviews Molecular Cell Biology.

[14]  W. Tao,et al.  Mice deficient of Lats1 develop soft-tissue sarcomas, ovarian tumours and pituitary dysfunction , 1999, Nature Genetics.

[15]  J. Downward,et al.  Akt phosphorylates the Yes-associated protein, YAP, to induce interaction with 14-3-3 and attenuation of p73-mediated apoptosis. , 2003, Molecular cell.

[16]  Jiandie D. Lin,et al.  TEAD mediates YAP-dependent gene induction and growth control. , 2008, Genes & development.

[17]  M. Nakafuku,et al.  Regulation of Gli2 and Gli3 activities by an amino-terminal repression domain: implication of Gli2 and Gli3 as primary mediators of Shh signaling. , 1999, Development.

[18]  H. Niwa,et al.  A novel mechanism for regulating clonal propagation of mouse ES cells , 2004, Genes to cells : devoted to molecular & cellular mechanisms.

[19]  Janet Rossant,et al.  Cdx2 acts downstream of cell polarization to cell-autonomously promote trophectoderm fate in the early mouse embryo. , 2008, Developmental biology.

[20]  K. Irvine,et al.  The Fat and Warts signaling pathways: new insights into their regulation, mechanism and conservation , 2008, Development.

[21]  J. Rossant,et al.  Potential of isolated mouse inner cell masses to form trophectoderm derivatives in vivo. , 1979, Developmental biology.

[22]  H. Ko,et al.  Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1 , 2007, Proceedings of the National Academy of Sciences.

[23]  A. Nose,et al.  Calcium-dependent cell-cell adhesion molecules (cadherins): subclass specificities and possible involvement of actin bundles , 1987, The Journal of cell biology.

[24]  Kevin J. Cheung,et al.  Tumor Suppressor LATS1 Is a Negative Regulator of Oncogene YAP* , 2008, Journal of Biological Chemistry.

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

[26]  Shian Wu,et al.  The TEAD/TEF family protein Scalloped mediates transcriptional output of the Hippo growth-regulatory pathway. , 2008, Developmental cell.

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

[28]  Jianmin Zhang,et al.  Negative regulation of YAP by LATS1 underscores evolutionary conservation of the Drosophila Hippo pathway. , 2008, Cancer research.

[29]  D. Pan,et al.  Hippo signaling in organ size control. , 2007, Genes & development.

[30]  D. Flagiello,et al.  SCALLOPED Interacts with YORKIE, the Nuclear Effector of the Hippo Tumor-Suppressor Pathway in Drosophila , 2008, Current Biology.

[31]  H. Kiyonari,et al.  Ssdp 1 regulates head morphogenesis of mouse embryos by activating the Lim 1-Ldb 1 complex , 2005 .

[32]  J. Rossant,et al.  Promotion of trophoblast stem cell proliferation by FGF4. , 1998, Science.

[33]  M. Thompson,et al.  Inhibition of the TEF/TEAD transcription factor activity by nuclear calcium and distinct kinase pathways. , 2003, Biochemical and biophysical research communications.

[34]  M. DePamphilis,et al.  TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. , 2001, Genes & development.

[35]  K. Mizuseki,et al.  Requirement of Sox2-mediated signaling for differentiation of early Xenopus neuroectoderm. , 2000, Development.

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

[37]  G. Feldmann,et al.  Elucidation of a Universal Size-Control Mechanism in Drosophila and Mammals , 2007, Cell.

[38]  C. Ziomek,et al.  The foundation of two distinct cell lineages within the mouse morula , 1981, Cell.

[39]  Esteban O. Mazzoni,et al.  The Growth Regulators warts/lats and melted Interact in a Bistable Loop to Specify Opposite Fates in Drosophila R8 Photoreceptors , 2005, Cell.

[40]  Zhengyu Zha,et al.  TAZ Promotes Cell Proliferation and Epithelial-Mesenchymal Transition and Is Inhibited by the Hippo Pathway , 2008, Molecular and Cellular Biology.

[41]  H. Sasaki,et al.  Mammalian Tead proteins regulate cell proliferation and contact inhibition as transcriptional mediators of Hippo signaling , 2008, Development.

[42]  B. Maro,et al.  A major posttranslational modification of ezrin takes place during epithelial differentiation in the early mouse embryo. , 2001, Developmental biology.

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

[44]  T P Fleming,et al.  A quantitative analysis of cell allocation to trophectoderm and inner cell mass in the mouse blastocyst. , 1987, Developmental biology.

[45]  M. Takeichi,et al.  The calcium-dependent cell-cell adhesion system regulates inner cell mass formation and cell surface polarization in early mouse development , 1983, Cell.

[46]  Guoji Guo,et al.  Role of Cdx2 and cell polarity in cell allocation and specification of trophectoderm and inner cell mass in the mouse embryo. , 2008, Genes & development.

[47]  A. Tarkowski,et al.  Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage. , 1967, Journal of embryology and experimental morphology.

[48]  Li Li,et al.  Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. , 2007, Genes & development.

[49]  M. Yaffe,et al.  The transcriptional co-activator TAZ interacts differentially with transcriptional enhancer factor-1 (TEF-1) family members. , 2005, The Biochemical journal.

[50]  A. Spindle,et al.  Trophoblast regeneration by inner cell masses isolated from cultured mouse embryos. , 1978, The Journal of experimental zoology.

[51]  C. Haipek,et al.  The NF2 tumor suppressor gene product, merlin, mediates contact inhibition of growth through interactions with CD44. , 2001, Genes & development.

[52]  G. Halder,et al.  The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis , 2006, Nature Cell Biology.

[53]  N. Tapon,et al.  The Tumor-Suppressor Gene fat Controls Tissue Growth Upstream of Expanded in the Hippo Signaling Pathway , 2006, Current Biology.

[54]  N. Ogonuki,et al.  Noninvasive visualization of molecular events in the mammalian zygote , 2005, Genesis.

[55]  K. Harvey,et al.  Fat Cadherin Modulates Organ Size in Drosophila via the Salvador/Warts/Hippo Signaling Pathway , 2006, Current Biology.

[56]  A. Smith,et al.  Self-renewal of pluripotent embryonic stem cells is mediated via activation of STAT3. , 1998, Genes & development.

[57]  J. Miyazaki,et al.  Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells , 2000, Nature Genetics.

[58]  Rika Nakayama,et al.  Tead proteins activate the Foxa2 enhancer in the node in cooperation with a second factor , 2005, Development.

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

[60]  H. Schöler,et al.  Oct-4 transcription factor is differentially expressed in the mouse embryo during establishment of the first two extraembryonic cell lineages involved in implantation. , 1994, Developmental biology.