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Placental development: Lessons from mouse mutants

Key Points

  • The placenta is critical for the development of mammalian embryos as it is needed for the exchange of gases, nutrients and waste products between mother and baby. The placenta is also a source of pregnancy-associated hormones and growth factors, and is involved in immune protection of the fetus. Despite its importance, little is known of the molecular basis of human placental disorders.

  • Placental abnormalities often underlie the embryonic lethality caused by the targeted mutation of mouse genes, and can arise from defects in the embryonic, trophoblast or maternal compartments of the placenta. Mouse mutants provide a vital resource for identifying and investigating the genes that control the differentiation and development of the placental cell lineages.

  • The most important lineage in the placenta is the trophoblast lineage, which provides the structural and functional components of the placenta that bring the fetal and maternal blood systems into contact.

  • The trophoblast lineage depends on several embryo-derived signals for its proliferation and differentiation. Among these are members of the fibroblast growth factor family, especially Fgf4, and the oestrogen-related receptor, Errβ.

  • The trophoblast is considered to be paramount in regulating the development of the fetal component of the placenta's vascular system because components of the key signalling pathways are only expressed in the trophoblast, and because chimaera and tetraploid-aggregation experiments have shown that their function is only required in this compartment.

  • Studies of placental development in mice should shed light on the molecular basis of certain human pregnancy disorders, such as pre-eclampsia and early pregnancy loss. Such advances will require a better understanding of the relationships between the different placental structures in mice and humans to test molecular similarities between the two species.

Abstract

The placenta is the first organ to form during mammalian embryogenesis. Problems in its formation and function underlie many aspects of early pregnancy loss and pregnancy complications in humans. Because the placenta is critical for survival, it is very sensitive to genetic disruption, as reflected by the ever-increasing list of targeted mouse mutations that cause placental defects. Recent studies of mouse mutants with disrupted placental development indicate that signalling interactions between the placental trophoblast and embryonic cells have a key role in placental morphogenesis. Furthering our understanding of mouse trophoblast development should provide novel insights into human placental function.

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Figure 1: Placental development in the mouse.
Figure 2: Comparative anatomy of the mouse and human placenta.
Figure 3: Regulation of chorioallantoic morphogenesis.

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References

  1. Cross, J. C. Genetic insights into trophoblast differentiation and placental morphogenesis. Semin. Cell Dev. Biol. 11, 105–113 (2000).

    CAS  PubMed  Google Scholar 

  2. Barak, Y. et al. PPAR gamma is required for placental, cardiac, and adipose tissue development. Mol. Cell 4, 585–595 (1999).

    CAS  PubMed  Google Scholar 

  3. Cross, J. C. et al. Trophoblast functions, angiogenesis and remodeling of the maternal vasculature in the placenta. Mol. Cell Endocrinol. (in the press).

  4. Damsky, C. H. & Fisher, S. J. Trophoblast pseudo-vasculogenesis: faking it with endothelial adhesion receptors. Curr. Opin. Cell Biol. 10, 660–666 (1998).

    CAS  PubMed  Google Scholar 

  5. Copp, A. J. Interaction between inner cell mass and trophectoderm of the mouse blastocyst. II. The fate of the polar trophectoderm. J. Embryol. Exp. Morphol. 51, 109–120 (1979).

    CAS  PubMed  Google Scholar 

  6. Soares, M. J. et al. Differentiation of trophoblast endocrine cells. Placenta 17, 277–289 (1996).

    CAS  PubMed  Google Scholar 

  7. Groskopf, J. C., Syu, L. J., Saltiel, A. R. & Linzer, D. I. Proliferin induces endothelial cell chemotaxis through a G protein-coupled, mitogen-activated protein kinase-dependent pathway. Endocrinology 138, 2835–2840 (1997).

    CAS  PubMed  Google Scholar 

  8. Vuorela, P. et al. Expression of vascular endothelial growth factor and placenta growth factor in human placenta. Biol. Reprod. 56, 489–494 (1997).

    CAS  PubMed  Google Scholar 

  9. Achen, M. G., Gad, J. M., Stacker, S. A. & Wilks, A. F. Placenta growth factor and vascular endothelial growth factor are co-expressed during early embryonic development. Growth Factors 15, 69–80 (1997).

    CAS  PubMed  Google Scholar 

  10. Teesalu, T., Masson, R., Basset, P., Blasi, F. & Talarico, D. Expression of matrix metalloproteinases during murine chorioallantoic placenta maturation. Dev. Dyn. 214, 248–258 (1999).

    CAS  PubMed  Google Scholar 

  11. Teesalu, T., Blasi, F. & Talarico, D. Expression and function of the urokinase type plasminogen activator during mouse hemochorial placental development. Dev. Dyn. 213, 27–38 (1998).

    CAS  PubMed  Google Scholar 

  12. Gardner, R. L., Papaioannou, V. E. & Barton, S. C. Origin of the ectoplacental cone and secondary giant cells in mouse blastocysts reconstituted from isolated trophectoderm and inner cell mass. J. Embryol. Exp. Morphol. 30, 561–572 (1973).

    CAS  PubMed  Google Scholar 

  13. Hunt, C. V. & Avery, G. B. The development and proliferation of the trophoblast from ectopic mouse embryo allografts of increasing gestational age. J. Reprod. Fertil. 46, 305–311 (1976).

    CAS  PubMed  Google Scholar 

  14. Jenkinson, E. J. & Billington, W. D. Differential susceptibility of mouse trophoblast and embryonic tissue to immune cell lysis. Transplantation 18, 286–289 (1974).

    CAS  PubMed  Google Scholar 

  15. Rossant, J. & Ofer, L. Properties of extra-embryonic ectoderm isolated from postimplantation mouse embryos. J. Embryol. Exp. Morphol. 39, 183–194 (1977).

    CAS  PubMed  Google Scholar 

  16. Rossant, J. & Tamara-Lis, W. Effect of culture conditions in diploid to giant-cell transformation in postimplantation mouse trophoblast. J. Embryol. Exp. Morphol. 62, 217–227 (1981).

    CAS  PubMed  Google Scholar 

  17. Ilgren, E. B. On the control of the trophoblastic giant-cell transformation in the mouse: homotypic cellular interactions and polyploidy. J. Embryol. Exp. Morphol. 62, 183–202 (1981).

    CAS  PubMed  Google Scholar 

  18. Johnson, M. H. & Rossant, J. Molecular studies on cells of the trophectoderm lineage of the postimplantation mouse embryo. J. Embryol. Exp. Morphol. 61, 103–116 (1981).

    CAS  PubMed  Google Scholar 

  19. Niswander, L. & Martin, G. R. Fgf-4 expression during gastrulation, myogenesis, limb and tooth development in the mouse. Development 114, 755–768 (1992).

    CAS  PubMed  Google Scholar 

  20. Rappolee, D. A., Basilico, C., Patel, Y. & Werb, Z. Expression and function of FGF-4 in peri-implantation development in mouse embryos. Development 120, 2259–2269 (1994).

    CAS  PubMed  Google Scholar 

  21. Feldman, B., Poueymirou, W., Papaioannou, V. E., DeChiara, T. M. & Goldfarb, M. Requirement of FGF-4 for postimplantation mouse development. Science 267, 246–249 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Wilder, P. J. et al. Inactivation of the FGF-4 gene in embryonic stem cells alters the growth and/or the survival of their early differentiated progeny. Dev. Biol. 192, 614–629 (1997).

    CAS  PubMed  Google Scholar 

  23. Chai, N. et al. FGF is an essential regulator of the fifth cell division in preimplantation mouse embryos. Dev. Biol. 198, 105–115 (1998).Reports that Fgf4 regulates trophectoderm differentiation.

    CAS  PubMed  Google Scholar 

  24. Nichols, J. et al. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell 95, 379–391 (1998).

    CAS  PubMed  Google Scholar 

  25. Tanaka, S., Kunath, T., Hadjantonakis, A. K., Nagy, A. & Rossant, J. Promotion of trophoblast stem cell proliferation by FGF4. Science 282, 2072–2075 (1998).The derivation of trophoblast stem cells from mouse blastocysts and early postimplantation embryos in the presence of Fgf4 and fibroblast-conditioned medium.

    CAS  PubMed  Google Scholar 

  26. Rappolee, D. A., Patel, Y. & Jacobson, K. Expression of fibroblast growth factor receptors in peri-implantation mouse embryos. Mol. Reprod. Dev. 51, 254–264 (1998).

    CAS  PubMed  Google Scholar 

  27. Haffner-Krausz, R., Gorivodsky, M., Chen, Y. & Lonai, P. Expression of Fgfr2 in the early mouse embryo indicates its involvement in preimplantation development. Mech. Dev. 85, 167–172 (1999).

    CAS  PubMed  Google Scholar 

  28. Arman, E., Haffner-Krausz, R., Chen, Y., Heath, J. K. & Lonai, P. Targeted disruption of fibroblast growth factor (FGF) receptor 2 suggests a role for FGF signaling in pregastrulation mammalian development. Proc. Natl Acad. Sci. USA 95, 5082–5087 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  29. Xu, X. et al. Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 125, 753–765 (1998).

    CAS  PubMed  Google Scholar 

  30. Isaacs, H. V., Pownall, M. E. & Slack, J. M. Regulation of Hox gene expression and posterior development by the Xenopus caudal homologue Xcad3. EMBO J. 17, 3413–3427 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Smith, J. C., Price, B. M. J., Green, J. B. A., Weigel, D. & Herrmann, B. G. Expression of a Xenopus homolog of Brachyury (T) is an immediate-early response to mesoderm induction. Cell 67, 79–87 (1991).

    CAS  PubMed  Google Scholar 

  32. Griffin, K. J., Amacher, S. L., Kimmel, C. B. & Kimelman, D. Molecular identification of spadetail: regulation of zebrafish trunk and tail mesoderm formation by T-box genes. Development 125, 3379–3388 (1998).

    CAS  PubMed  Google Scholar 

  33. Beck, F., Chawengsaksophak, K., Waring, P., Playford, R. J. & Furness, J. B. Reprogramming of intestinal differentiation and intercalary regeneration in Cdx2 mutant mice. Proc. Natl Acad. Sci. USA 96, 7318–7323 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Russ, A. P. et al. Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 404, 95–99 (2000).

    CAS  PubMed  Google Scholar 

  35. Ciruna, B. G. & Rossant, J. Expression of the T-box gene Eomesodermin during early mouse development. Mech. Dev. 81, 199–203 (1999).

    CAS  PubMed  Google Scholar 

  36. Chawengsaksophak, K., James, R., Hammond, V. E., Kontgen, F. & Beck, F. Homeosis and intestinal tumours in Cdx2 mutant mice. Nature 386, 84–87 (1997).

    CAS  PubMed  Google Scholar 

  37. Pettersson, K. et al. Expression of a novel member of estrogen response element-binding nuclear receptors is restricted to the early stages of chorion formation during mouse embryogenesis. Mech. Dev. 54, 211–223 (1996).

    CAS  PubMed  Google Scholar 

  38. Luo, J. et al. Placental abnormalities in mouse embryos lacking the orphan nuclear receptor ERR-beta. Nature 388, 778–782 (1997).

    CAS  PubMed  Google Scholar 

  39. Tremblay, G. B. et al. Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERRbeta. Genes Dev. 15, 833–838 (2001).An antagonist of the orphan nuclear hormone receptor, ERRβ, promotes trophoblast-stem-cell differentiation in vivo and in vitro.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Yan, J. et al. Retinoic acid promotes differentiation of trophoblast stem cells to a giant cell fate. Dev. Biol. (in the press).

  41. Gurtner, G. C. et al. Targeted disruption of the murine VCAM1 gene: essential role of VCAM-1 in chorioallantoic fusion and placentation. Genes Dev. 9, 1–14 (1995).

    CAS  PubMed  Google Scholar 

  42. Kwee, L. et al. Defective development of the embryonic and extraembryonic circulatory systems in vascular cell adhesion molecule (VCAM-1) deficient mice. Development 121, 489–503 (1995).

    CAS  PubMed  Google Scholar 

  43. Yang, J. T., Rayburn, H. & Hynes, R. O. Cell adhesion events mediated by alpha-4 integrins are essential in placental and cardiac development. Development 121, 549–560 (1995).

    CAS  PubMed  Google Scholar 

  44. Hunter, P. J., Swanson, B. J., Haendel, M. A., Lyons, G. E. & Cross, J. C. Mrj encodes a DnaJ-related co-chaperone that is essential for murine placental development. Development 126, 1247–1258 (1999).

    CAS  PubMed  Google Scholar 

  45. Anson-Cartwright, L. et al. The glial cells missing-1 protein is essential for branching morphogenesis in the chorioallantoic placenta. Nature Genet. 25, 311–314 (2000).Gcm1 expression marks sites of allantoic invasion and is required for villus branching in the labyrinth.

    CAS  PubMed  Google Scholar 

  46. Schreiber, J. et al. Placental failure in mice lacking the mammalian homolog of glial cells missing, GCMa. Mol. Cell. Biol. 20, 2466–2474 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Basyuk, E. et al. The murine Gcm1 gene is expressed in a subset of placental trophoblast cells. Dev. Dyn. 214, 303–311 (1999).

    CAS  PubMed  Google Scholar 

  48. Hernandez-Verdun, D. Morphogenesis of the syncytium in the mouse placenta. Ultrastructural study. Cell Tissue Res. 148, 381–396 (1974).

    CAS  PubMed  Google Scholar 

  49. Hemberger, M. & Cross, J. C. Genes governing placental development. Trends Endocrin. Metab. 12, 162–168 (2001).

    CAS  Google Scholar 

  50. Nogawa, H. & Ito, T. Branching morphogenesis of embryonic mouse lung epithelium in mesenchyme-free culture. Development 121, 1015–1022 (1995).

    CAS  PubMed  Google Scholar 

  51. Arman, E., Haffner-Krausz, R., Gorivodsky, M. & Lonai, P. Fgfr2 is required for limb outgrowth and lung-branching morphogenesis. Proc. Natl Acad. Sci. USA 96, 11895–11899 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Dudley, A. T., Godin, R. E. & Robertson, E. J. Interaction between FGF and BMP signaling pathways regulates development of metanephric mesenchyme. Genes Dev. 13, 1601–1613 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Skaer, H. Morphogenesis: FGF branches out. Curr. Biol. 7, R238–R241 (1997).

    CAS  PubMed  Google Scholar 

  54. Cheng, A. M. et al. Mammalian Grb2 regulates multiple steps in embryonic development, lineage commitment and malignant transformation. Cell 95, 793–803 (1998).

    CAS  PubMed  Google Scholar 

  55. Saxton, T. M. et al. Gene dosage dependent functions for phosphotyrosine–Grb2 signaling during mammalian tissue morphogenesis. Curr. Biol. 11, 662–670 (2001).

    CAS  PubMed  Google Scholar 

  56. Itoh, M. et al. Role of Gab1 in heart, placenta, and skin development and growth factor- and cytokine-induced extracellular signal-regulated kinase mitogen-activated protein kinase activation. Mol. Cell. Biol. 20, 3695–3704 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  57. Qian, X. et al. The Sos1 and Sos2 Ras-specific exchange factors: differences in placental expression and signaling properties. EMBO J. 19, 642–654 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Giroux, S. et al. Embryonic death of Mek1-deficient mice reveals a role for this kinase in angiogenesis in the labyrinthine region of the placenta. Curr. Biol. 9, 369–372 (1999).

    CAS  PubMed  Google Scholar 

  59. Adams, R. H. et al. Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol. Cell 6, 109–116 (2000).

    CAS  PubMed  Google Scholar 

  60. Yang, J. et al. Mekk3 is essential for early embryonic cardiovascular development. Nature Genet. 24, 309–313 (2000).

    CAS  PubMed  Google Scholar 

  61. Galceran, J., Farinas, I., Depew, M. J., Clevers, H. & Grosschedl, R. Wnt3a−/− like phenotype and limb deficiency in Lef1(−/−)Tcf1(−/−) mice. Genes Dev. 13, 709–717 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Monkley, S. J., Delaney, S. J., Pennisi, D. J., Christiansen, J. H. & Wainwright, B. J. Targeted disruption of the Wnt2 gene results in placentation defects. Development 122, 3343–3353 (1996).

    CAS  PubMed  Google Scholar 

  63. Ishikawa, T. et al. Mouse Wnt receptor gene Fzd5 is essential for yolk sac and placental angiogenesis. Development 128, 25–33 (2001).

    CAS  PubMed  Google Scholar 

  64. Castellucc, M., Kosanke, G., Verdenelli, F., Huppertz, B. & Kaufmann, P. Villous sprouting: fundamental mechanisms of human placental development. Hum. Reprod. Update 6, 485–494 (2000).

    Google Scholar 

  65. Burrow, C. R. Regulatory molecules in kidney development. Pediatr. Nephrol. 14, 240–253 (2000).

    CAS  PubMed  Google Scholar 

  66. Warburton, D. et al. The molecular basis of lung morphogenesis. Mech. Dev. 92, 55–81 (2000).

    CAS  PubMed  Google Scholar 

  67. Li, Y., Lemaire, P. & Behringer, R. R. Esx1, a novel X chromosome-linked homeobox gene expressed in mouse extraembryonic tissues and male germ cells. Dev. Biol. 188, 85–95 (1997).

    CAS  PubMed  Google Scholar 

  68. Li, Y. & Behringer, R. R. Esx1 is an X-chromosome-imprinted regulator of placental development and fetal growth. Nature Genet. 20, 309–311 (1998).

    CAS  PubMed  Google Scholar 

  69. Adelman, D. M., Gertsenstein, M., Nagy, A., Simon, M. C. & Maltepe, E. Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev. 14, 3191–3203 (2000).Reports the use of trophoblast stem cells and tetraploid aggregation assays to show that Arnt functions to regulate trophoblast cell fate and function, as well as hypoxia responses.

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Kozak, K. R., Abbott, B. & Hankinson, O. ARNT-deficient mice and placental differentiation. Dev. Biol. 191, 297–305 (1997).

    CAS  PubMed  Google Scholar 

  71. Maltepe, E. & Simon, M. C. Oxygen, genes, and development: an analysis of the role of hypoxic gene regulation during murine vascular development. J. Mol. Med. 76, 391–401 (1998).

    CAS  PubMed  Google Scholar 

  72. Caniggia, I. et al. Hypoxia-inducible factor-1 mediates the biological effects of oxygen on human trophoblast differentiation through TGFbeta(3). J. Clin. Invest. 105, 577–587 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Genbacev, O., Zhou, Y., Ludlow, J. W. & Fisher, S. J. Regulation of human placental development by oxygen tension. Science 277, 1669–1672 (1997).Shows that hypoxia affects human trophoblast development and that it is probably an important regulator of placental function.

    CAS  PubMed  Google Scholar 

  74. Zybina, E. V. & Zybina, T. G. Polytene chromosomes in mammalian cells. Int. Rev. Cytol. 165, 53–119 (1996).

    CAS  PubMed  Google Scholar 

  75. MacAuley, A., Cross, J. C. & Werb, Z. Reprogramming the cell cycle for endoreduplication in rodent trophoblast cells. Mol. Biol. Cell 9, 795–807 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Berezowsky, J., Zbieranowski, I., Demers, J. & Murray, D. DNA ploidy of hydatidiform moles and nonmolar conceptuses: a study using flow and tissue section image cytometry. Mod. Pathol. 8, 775–781 (1995).

    CAS  PubMed  Google Scholar 

  77. Alders, M. et al. The human Achaete-Scute homologue 2 (ASCL2, HASH2) maps to chromosome 11p15. 5, close to IGF2 and is expressed in extravillus trophoblasts. Hum. Mol. Genet. 6, 859–867 (1997).

    CAS  PubMed  Google Scholar 

  78. Janatpour, M. J. et al. A repertoire of differentially expressed transcription factors that offers insight into mechanisms of human cytotrophoblast differentiation. Dev. Genet. 25, 146–157 (1999).

    CAS  PubMed  Google Scholar 

  79. Knofler, M., Meinhardt, G., Vasicek, R., Husslein, P. & Egarter, C. Molecular cloning of the human Hand1 gene/cDNA and its tissue-restricted expression in cytotrophoblastic cells and heart. Gene 224, 77–86 (1998).

    CAS  PubMed  Google Scholar 

  80. Nait-Oumesmar, B., Copperman, A. B. & Lazzarini, R. A. Placental expression and chromosomal localization of the human Gcm 1 gene. J. Histochem. Cytochem. 48, 915–922 (2000).

    CAS  PubMed  Google Scholar 

  81. Somerset, D. A. et al. Ontogeny of hepatocyte growth factor (HGF) and its receptor (c-met) in human placenta: reduced HGF expression in intrauterine growth restriction. Am. J. Pathol. 153, 1139–1147 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Cross, J. C. Trophoblast function in normal and preeclamptic pregnancy. Fet. Mat. Med. Rev. 8, 57–66 (1996).

    Google Scholar 

  83. Meegdes, B. H., Ingenhoes, R., Peeters, L. L. & Exalto, N. Early pregnancy wastage: relationship between chorionic vascularization and embryonic development. Fertil. Steril. 49, 216–220 (1988).

    CAS  PubMed  Google Scholar 

  84. Ornoy, A., Salamon-Arnon, J., Ben-Zur, Z. & Kohn, G. Placental findings in spontaneous abortions and stillbirths. Teratology 24, 243–252 (1981).

    CAS  PubMed  Google Scholar 

  85. van Lijnschoten, G., Arends, J. W. & Geraedts, J. P. Comparison of histological features in early spontaneous and induced trisomic abortions. Placenta 15, 765–773 (1994).

    CAS  PubMed  Google Scholar 

  86. Krebs, C. et al. Intrauterine growth restriction with absent end-diastolic flow velocity in the umbilical artery is associated with maldevelopment of the placental terminal villous tree. Am. J. Obstet. Gynecol. 175, 1534–1542 (1996).

    CAS  PubMed  Google Scholar 

  87. Nagy, A. et al. Embryonic stem cells alone are able to support fetal development in the mouse. Development 110, 815–821 (1990).

    CAS  PubMed  Google Scholar 

  88. Nagy, A., Rossant, J., Nagy, R., Abramow-Newerly, W. & Roder, J. C. Derivation of completely cell culture-derived mice from early-passage embryonic stem cells. Proc. Natl Acad. Sci. USA 90, 8424–8428 (1993).Reported the use of tetraploid-aggregation chimaeras for making embryonic-stem-cell-derived mice.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Tanaka, M., Gertsenstein, M., Rossant, J. & Nagy, A. Mash2 acts cell autonomously in mouse spongiotrophoblast development. Dev. Biol. 190, 55–65 (1997).

    CAS  PubMed  Google Scholar 

  90. Guillemot, F., Nagy, A., Auerbach, A., Rossant, J. & Joyner, A. L. Essential role of Mash-2 in extraembryonic development. Nature 371, 333–336 (1994).

    CAS  PubMed  Google Scholar 

  91. Voss, A. K., Thomas, T. & Gruss, P. Mice lacking HSP90beta fail to develop a placental labyrinth. Development 127, 1–11 (2000).

    CAS  PubMed  Google Scholar 

  92. Schreiber, M. et al. Placental vascularisation requires the AP-1 component fra1. Development 127, 4937–4948 (2000).

    CAS  PubMed  Google Scholar 

  93. Schorpp-Kistner, M., Wang, Z. Q., Angel, P. & Wagner, E. F. JunB is essential for mammalian placentation. EMBO J. 18, 934–948 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Kraut, N., Snider, L., Chen, C. M., Tapscott, S. J. & Groudine, M. Requirement of the mouse I-mfa gene for placental development and skeletal patterning. EMBO J. 17, 6276–6288 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  95. Yamamoto, H. et al. Defective trophoblast function in mice with a targeted mutation of Ets2. Genes Dev. 12, 1315–1326 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Threadgill, D. W. et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269, 230–234 (1995).

    CAS  PubMed  Google Scholar 

  97. Sibilia, M. & Wagner, E. F. Strain-dependent epithelial defects in mice lacking the EGF receptor. Science 269, 234–238 (1995).

    CAS  PubMed  Google Scholar 

  98. Xiao, X. et al. HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory responses in mice. EMBO J. 18, 5943–5952 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Solloway, M. J. & Robertson, E. J. Early embryonic lethality in Bmp5;Bmp7 double mutant mice suggests functional redundancy within the 60A subgroup. Development 126, 1753–1768 (1999).

    CAS  PubMed  Google Scholar 

  100. Li, E., Bestor, T. H. & Jaenisch, R. Targeted mutation of the DNA methyltransferase gene results in embryonic lethality. Cell 69, 915–926 (1992).

    CAS  PubMed  Google Scholar 

  101. Shawlot, W. & Behringer, R. R. Requirement for Lim1 in head-organizer function. Nature 374, 425–430 (1995).

    CAS  PubMed  Google Scholar 

  102. Rashbass, P., Cooke, L. A., Herrmann, B. G. & Beddington, R. S. P. A cell autonomous function of Brachyury in T/T embryonic stem cell chimaeras. Nature 353, 348–349 (1991).

    CAS  PubMed  Google Scholar 

  103. Morasso, M. I., Grinberg, A., Robinson, G., Sargent, T. D. & Mahon, K. A. Placental failure in mice lacking the homeobox gene Dlx3. Proc. Natl Acad. Sci. USA 96, 162–167 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Kruger, O. et al. Defective vascular development in connexin 45-deficient mice. Development 127, 4179–4193 (2000).

    CAS  PubMed  Google Scholar 

  105. Uehara, Y. et al. Placental defect and embryonic lethality in mice lacking hepatocyte growth factor/scatter factor. Nature 373, 702–705 (1995).

    CAS  PubMed  Google Scholar 

  106. Goh, K. L., Yang, J. T. & Hynes, R. O. Mesodermal defects and cranial neural crest apoptosis in alpha5 integrin-null embryos. Development 124, 4309–4319 (1997).

    CAS  PubMed  Google Scholar 

  107. Ware, C. B. et al. Targeted disruption of the low-affinity leukemia inhibitory factor receptor gene causes placental, skeletal, neural and metabolic defects and results in perinatal death. Development 121, 1283–1299 (1995).

    CAS  PubMed  Google Scholar 

  108. Bladt, F., Riethmacher, D., Isenmann, S., Aguzzi, A. & Birchmeier, C. Essential role for the c-met receptor in the migration of myogenic precursor cells into the limb bud. Nature 376, 768–771 (1995).

    CAS  PubMed  Google Scholar 

  109. Ohlsson, R. et al. PDGFB regulates the development of the labyrinthine layer of the mouse fetal placenta. Dev. Biol. 212, 124–136 (1999).

    CAS  PubMed  Google Scholar 

  110. Wendling, O., Chambon, P. & Mark, M. Retinoid X receptors are essential for early mouse development and placentogenesis. Proc. Natl Acad. Sci. USA 96, 547–551 (1999).

    CAS  PubMed  PubMed Central  Google Scholar 

  111. Gnarra, J. R. et al. Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc. Natl Acad. Sci. USA 94, 9102–9107 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  112. Steingrimsson, E., Tessarollo, L., Reid, S. W., Jenkins, N. A. & Copeland, N. G. The bHLH-Zip transcription factor Tfeb is essential for placental vascularization. Development 125, 4607–4616 (1998).

    CAS  PubMed  Google Scholar 

  113. Gabriel, H. D. et al. Transplacental uptake of glucose is decreased in embryonic lethal connexin26-deficient mice. J. Cell Biol. 140, 1453–1461 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  114. Riley, P., Anson-Cartwright, L. & Cross, J. C. The Hand1 bHLH transcription factor is essential for placentation and cardiac morphogenesis. Nature Genet. 18, 271–275 (1998).

    CAS  PubMed  Google Scholar 

  115. Ogura, Y., Takakura, N., Yoshida, H. & Nishikawa, S. I. Essential role of platelet-derived growth factor receptor alpha in the development of the intraplacental yolk sac/sinus of Duval in mouse placenta. Biol. Reprod. 58, 65–72 (1998).

    CAS  PubMed  Google Scholar 

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Acknowledgements

The work of the authors that is described here is supported by the Canadian Institutes of Health Research (CIHR). J.C. is an Investigator of the CIHR and Senior Scholar of the Alberta Heritage Foundation for Medical Research (AHFMR), and J.R. is a Distinguished Investigator of the CIHR.

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Authors

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DATABASE LINKS

Mash2

Hand1

PPARγ

placental lactogens

proliferin

VEGF

MMPs

uPA

Fgf4

Oct4

Fgfr2

Cdx2

Eomes

Errb

Brachyury

Bmp5

Bmp7

Vcam1

Itga4

Gcm1

Lifr

Egfr

Met

Grb2

Gab1

Sos1

Mek1

ERK1

ERK2

p38α MAP kinase

Mekk3

Tcf1

Lef1

Wnt2

Fzd5

Esx1

Arnt

EPAS1

Hgf

FURTHER INFORMATION

Catalogue of mouse placental mutants

Janet Rossant's lab

James Cross's lab

Glossary

TROPHOBLAST

The postimplantation derivatives of the trophectoderm, which make up most of the fetal part of the placenta.

DECIDUA

The lining of the uterus (the endometrium) that surrounds the embryo, which becomes transformed in pregnancy.

TROPHECTODERM

The outer epithelial layer of the blastocyst.

BLASTOCYST

An early stage of mammalian embryonic development at which the first cell lineages become established.

INNER CELL MASS

(ICM). A small clump of apparently undifferentiated cells in the blastocyst, which gives rise to the entire fetus plus some of its extra-embryonic membranes.

IMPLANTATION

The process of embedding the embryo into the lining of the uterus.

EXTRA-EMBRYONIC ECTODERM

A diploid derivative of the early postimplantation trophoblast, which probably gives rise to the labyrinthine trophoblast.

ECTOPLACENTAL CONE

A diploid derivative of the early postimplantation trophoblast, which probably gives rise to the spongiotrophoblast.

ENDOREDUPLICATION

Repeated rounds of DNA replication in the absence of intervening mitoses, which lead to polyploidy.

TROPHOBLAST GIANT CELLS

Non-dividing polyploid cells of the rodent placenta that are formed by endoreduplication.

CHORION

An extra-embryonic membrane that consists of mesothelium and ectoderm (the ectoderm is derived from the trophoblast in mammals). The allantois attaches to this membrane to form the chorioallantoic membrane in birds, and the chorioallantoic placenta in mammals.

ALLANTOIS

A mesoderm-derived structure that emerges from the posterior end of the embryo and attaches to the placenta. It gives rise to the placental blood vessels and the umbilical cord, which are necessary for carrying nutrients and waste products between the growing fetus and the placenta.

PLACENTAL LABYRINTH

The area of direct exchange between the fetal and maternal blood supply in the mammalian placenta.

LABYRINTHINE TROPHOBLAST

The trophoblast cells of the labyrinth (mostly syncytiotrophoblast, some giant cells and smaller mononuclear cells).

SYNCYTIOTROPHOBLAST

Multinucleate trophoblast cells that occupy the placental labyrinth in mice.

SPONGIOTROPHOBLAST

The outer structural layer of the rodent placenta.

EPIBLAST

One of the layers of cells in the early embryo, which gives rise to all three definitive germ layers of the embryo: ectoderm, mesoderm and endoderm.

HYPOMORPH

A mutant allele that does not eliminate the wild-type function of a gene and gives a less severe phenotype than a loss-of-function mutant.

CYTOTROPHOBLAST

In humans, a mononuclear cell that is the precursor cell of all other trophoblasts. Undifferentiated cytotrophoblasts can develop into three cell types: hormonally active villous syncytiotrophoblasts; extra-villous anchoring trophoblastic cell columns; or invasive trophoblasts.

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Rossant, J., Cross, J. Placental development: Lessons from mouse mutants. Nat Rev Genet 2, 538–548 (2001). https://doi.org/10.1038/35080570

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