Roles of Hippo Signaling During Mouse Embryogenesis

  • Hiroshi SasakiEmail author


Embryos undergo dynamic morphological changes during embryogenesis, and elaborate the basic body plan of adults from a single fertilized egg. The Hippo signaling pathway, originally identified as a tumor suppressor signaling pathway in Drosophila, is conserved in mice and controls intercellular communication by cell–cell contacts. Recent studies of mouse mutants reveal the roles of Hippo pathway components in the various stages of embryogenesis. Hippo signaling not only regulates cell proliferation and apoptosis but also controls cell fate specification. In this review, I summarize the roles of Hippo signaling during early embryogenesis and discuss the conservation and divergence of the roles and pathways in flies and mice depending upon the developmental stages.


Mouse development Preimplantation development Embryogenesis Trophectoderm Notochord Cell proliferation 


  1. Ang SL, Rossant J. HNF-3 β is essential for node and notochord formation in mouse development. Cell. 1994;78(4):561–74.PubMedCrossRefGoogle Scholar
  2. Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 2003;17(1):126–40.PubMedCrossRefGoogle Scholar
  3. Alarcon VB. Cell polarity regulator PARD6B is essential for trophectoderm formation in the preimplantation mouse embryo. Biol Reprod. 2010;83(3):347–58. doi:biolreprod.110.084400 [pii]  10.1095/biolreprod.110.084400.PubMedCrossRefGoogle Scholar
  4. Chen CL, Gajewski KM, Hamaratoglu F, Bossuyt W, Sansores-Garcia L, Tao C, et al. The apical-basal cell polarity determinant Crumbs regulates Hippo signaling in Drosophila. Proc Natl Acad Sci U S A. 2010;107(36):15810–5. doi:1004060107 [pii]  10.1073/pnas.1004060107.PubMedCrossRefGoogle Scholar
  5. Chen L, Yabuuchi A, Eminli S, Takeuchi A, Lu CW, Hochedlinger K, et al. Cross-regulation of the Nanog and Cdx2 promoters. Cell Res. 2009;19(9):1052–61. doi:cr200979 [pii]  10.1038/cr.2009.79.PubMedCrossRefGoogle Scholar
  6. Chen Z, Friedrich GA, Soriano P. Transcriptional enhancer factor 1 disruption by a retroviral gene trap leads to heart defects and embryonic lethality in mice. Genes Dev. 1994;8(19):2293–301.PubMedCrossRefGoogle Scholar
  7. Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, et al. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003;113(5):643–55.PubMedCrossRefGoogle Scholar
  8. Dietrich JE, Hiiragi T. Stochastic patterning in the mouse pre-implantation embryo. Development. 2007;134(23):4219–31.PubMedCrossRefGoogle Scholar
  9. Grzeschik NA, Parsons LM, Allott ML, Harvey KF, Richardson HE. Lgl, aPKC, and Crumbs regulate the Salvador/Warts/Hippo pathway through two distinct mechanisms. Curr Biol. 2010;20(7):573–81. doi:S0960-9822(10)00151-X [pii]  10.1016/j.cub.2010.01.055.PubMedCrossRefGoogle Scholar
  10. Halder G, Johnson RL. Hippo signaling: growth control and beyond. Development. 2011;138(1):9–22. doi:138/1/9 [pii]  10.1242/dev.045500.PubMedCrossRefGoogle Scholar
  11. Hirate Y, Cockburn K, Rossant J, Sasaki H. Tead4 is constitutively nuclear, while nuclear vs. cytoplasmic Yap distribution is regulated in preimplantation embryos. Proc. Natl. Acad. Sci. USA. 2012;109:E3389-90. doi: 10.1073/pnas.1211810109.PubMedCrossRefGoogle Scholar
  12. Home P, Saha B, Ray S, Dutta D, Gunewardena S, Yoo B, et al. Altered subcellular localization of transcription factor TEAD4 regulates first mammalian cell lineage commitment. Proc Natl Acad Sci U S A. 2012;109(19):7362–7. doi: 10.1073/pnas.1201595109.PubMedCrossRefGoogle Scholar
  13. Hossain Z, Ali SM, Ko HL, Xu J, Ng CP, Guo K, et al. Glomerulocystic kidney disease in mice with a targeted inactivation of Wwtr1. Proc Natl Acad Sci U S A. 2007;104(5):1631–6.PubMedCrossRefGoogle Scholar
  14. Kaneko KJ, Kohn MJ, Liu C, Depamphilis ML. Transcription factor TEAD2 is involved in neural tube closure. Genesis. 2007;45(9):577–87.PubMedCrossRefGoogle Scholar
  15. Lu L, Li Y, Kim SM, Bossuyt W, Liu P, Qiu Q, et al. Hippo signaling is a potent in vivo growth and tumor suppressor pathway in the mammalian liver. Proc Natl Acad Sci U S A. 2010;107(4):1437–42. doi:0911427107 [pii]  10.1073/pnas.0911427107.PubMedCrossRefGoogle Scholar
  16. Lee JH, Kim TS, Yang TH, Koo BK, Oh SP, Lee KP, et al. A crucial role of WW45 in developing epithelial tissues in the mouse. EMBO J. 2008;27(8):1231–42.PubMedCrossRefGoogle Scholar
  17. Ling C, Zheng Y, Yin F, Yu J, Huang J, Hong Y, et al. The apical transmembrane protein Crumbs functions as a tumor suppressor that regulates Hippo signaling by binding to Expanded. Proc Natl Acad Sci U S A. 2010;107(23):10532–7. doi:1004279107 [pii]  10.1073/pnas.1004279107.PubMedCrossRefGoogle Scholar
  18. Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, et al. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 2003;113(5):631–42.PubMedCrossRefGoogle Scholar
  19. Makita R, Uchijima Y, Nishiyama K, Amano T, Chen Q, Takeuchi T, et al. Multiple renal cysts, urinary concentration defects, and pulmonary emphysematous changes in mice lacking TAZ. Am J Physiol. 2008;294(3):F542–53.Google Scholar
  20. McClatchey AI, Saotome I, Ramesh V, Gusella JF, Jacks T. The Nf2 tumor suppressor gene product is essential for extraembryonic development immediately prior to gastrulation. Genes Dev. 1997;11(10):1253–65.PubMedCrossRefGoogle Scholar
  21. McPherson JP, Tamblyn L, Elia A, Migon E, Shehabeldin A, Matysiak-Zablocki E, et al. Lats2/Kpm is required for embryonic development, proliferation control and genomic integrity. EMBO J. 2004;23(18):3677–88.PubMedCrossRefGoogle Scholar
  22. Morin-Kensicki EM, Boone BN, Howell M, Stonebraker JR, Teed J, Alb JG, et al. Defects in yolk sac vasculogenesis, chorioallantoic fusion, and embryonic axis elongation in mice with targeted disruption of Yap65. Mol Cell Biol. 2006;26(1):77–87.PubMedCrossRefGoogle Scholar
  23. Niwa H, Toyooka Y, Shimosato D, Strumpf D, Takahashi K, Yagi R, et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell. 2005;123(5):917–29.PubMedCrossRefGoogle Scholar
  24. Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998;95(3):379–91.PubMedCrossRefGoogle Scholar
  25. Nishioka N, Yamamoto S, Kiyonari H, Sato H, Sawada A, Ota M, et al. Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mech Dev. 2008;125(3–4):270–83.PubMedCrossRefGoogle Scholar
  26. Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, et al. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell. 2009;16(3):398–410.PubMedCrossRefGoogle Scholar
  27. Ota M, Sasaki H. Mammalian Tead proteins regulate cell proliferation and contact inhibition as a transcriptional mediator of Hippo signaling. Development. 2008;135:4059–69.PubMedCrossRefGoogle Scholar
  28. Overholtzer M, Zhang J, Smolen GA, Muir B, Li W, Sgroi DC, et al. Transforming properties of YAP, a candidate oncogene on the chromosome 11q22 amplicon. Proc Natl Acad Sci U S A. 2006;103(33):12405–10.PubMedCrossRefGoogle Scholar
  29. Pan D. The hippo signaling pathway in development and cancer. Dev Cell. 2010;19(4):491–505. doi:S1534-5807(10)00429-6 [pii]  10.1016/j.devcel.2010.09.011.PubMedCrossRefGoogle Scholar
  30. Ralston A, Cox BJ, Nishioka N, Sasaki H, Chea E, Rugg-Gunn P, et al. Gata3 regulates trophoblast development downstream of Tead4 and in parallel to Cdx2. Development. 2010;137(3):395–403. doi:137/3/395 [pii]  10.1242/dev.038828.PubMedCrossRefGoogle Scholar
  31. Robinson BS, Huang J, Hong Y, Moberg KH. Crumbs regulates Salvador/Warts/Hippo signaling in Drosophila via the FERM-domain protein Expanded. Curr Biol. 2010;20(7):582–90. doi:S0960-9822(10)00338-6 [pii]  10.1016/j.cub.2010.03.019.PubMedCrossRefGoogle Scholar
  32. Sawada A, Kiyonari H, Ukita K, Nishioka N, Imuta Y, Sasaki H. Redundant roles of Tead1 and Tead2 in notochord development and the regulation of cell proliferation and survival. Mol Cell Biol. 2008;28(10):3177–89.PubMedCrossRefGoogle Scholar
  33. Stanger BZ. Quit your YAPing: a new target for cancer therapy. Genes Dev. 2012;26(12):1263–7. doi: 10.1101/gad.196501.112.PubMedCrossRefGoogle Scholar
  34. Strumpf D, Mao CA, Yamanaka Y, Ralston A, Chawengsaksophak K, Beck F, et al. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development. 2005;132(9):2093–102.PubMedCrossRefGoogle Scholar
  35. Song H, Mak KK, Topol L, Yun K, Hu J, Garrett L, et al. Mammalian Mst1 and Mst2 kinases play essential roles in organ size control and tumor suppression. Proc Natl Acad Sci U S A. 2010;107(4):1431–6. doi:0911409107 [pii]  10.1073/pnas.0911409107.PubMedCrossRefGoogle Scholar
  36. Shimono A, Behringer RR. Angiomotin regulates visceral endoderm movements during mouse embryogenesis. Curr Biol. 2003;13(7):613–7. doi: S0960982203002045 [pii].PubMedCrossRefGoogle Scholar
  37. Sawada A, Nishizaki Y, Sato H, Yada Y, Nakayama R, Yamamoto S, et al. Tead proteins activate the Foxa2 enhancer in the node in cooperation with a second factor. Development. 2005;132(21):4719–29.PubMedCrossRefGoogle Scholar
  38. Vassilev A, Kaneko KJ, Shu H, Zhao Y, DePamphilis ML. TEAD/TEF transcription factors utilize the activation domain of YAP65, a Src/Yes-associated protein localized in the cytoplasm. Genes Dev. 2001;15(10):1229–41.PubMedCrossRefGoogle Scholar
  39. Varelas X, Samavarchi-Tehrani P, Narimatsu M, Weiss A, Cockburn K, Larsen BG, et al. The Crumbs complex couples cell density sensing to Hippo-dependent control of the TGF-beta-SMAD pathway. Dev Cell. 2010;19(6):831–44. doi:S1534-5807(10)00539-3 [pii]  10.1016/j.devcel.2010.11.012.PubMedCrossRefGoogle Scholar
  40. Weinstein DC, Ruiz i Altaba A, Chen WS, Hoodless P, Prezioso VR, Jessell TM, et al. The winged-helix transcription factor HNF-3 β is required for notochord development in the mouse embryo. Cell. 1994;78(4):575–88.PubMedCrossRefGoogle Scholar
  41. Xiao Z, Patrakka J, Nukui M, Chi L, Niu D, Betsholtz C, et al. Deficiency in Crumbs homolog 2 (Crb2) affects gastrulation and results in embryonic lethality in mice. Dev Dyn. 2011;240(12):2646–56. doi: 10.1002/dvdy.22778.PubMedCrossRefGoogle Scholar
  42. Yagi R, Kohn MJ, Karavanova I, Kaneko KJ, Vullhorst D, Depamphilis ML, et al. Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian d­evelopment. Development. 2007;134(21):3827–36.PubMedCrossRefGoogle Scholar
  43. Yabuta N, Okada N, Ito A, Hosomi T, Nishihara S, Sasayama Y, et al. Lats2 is an essential mitotic regulator required for the coordination of cell division. J Biol Chem. 2007;282(26):19259–71.PubMedCrossRefGoogle Scholar
  44. Zhao B, Ye X, Yu J, Li L, Li W, Li S, et al. TEAD mediates YAP-dependent gene induction and growth control. Genes Dev. 2008;22(14):1962–71.PubMedCrossRefGoogle Scholar
  45. Zhao B, Li L, Lei Q, Guan KL. The Hippo-YAP pathway in organ size control and tumorigenesis: an updated version. Genes Dev. 2010;24(9):862–74. doi: 10.1101/gad.1909210.PubMedCrossRefGoogle Scholar
  46. Zhao B, Wei X, Li W, Udan RS, Yang Q, Kim J, et al. Inactivation of YAP oncoprotein by the Hippo pathway is involved in cell contact inhibition and tissue growth control. Genes Dev. 2007;21(21):2747–61.PubMedCrossRefGoogle Scholar
  47. Zhou D, Conrad C, Xia F, Park JS, Payer B, Yin Y, et al. Mst1 and Mst2 maintain hepatocyte quiescence and suppress hepatocellular carcinoma development through inactivation of the Yap1 oncogene. Cancer Cell. 2009;16(5):425–38. doi:S1535-6108(09)00337-7 [pii]  10.1016/j.ccr.2009.09.026.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.Department of Cell Fate Control, Institute of Molecular Embryology and GeneticsKumamoto UniversityKumamotoJapan

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