Developmental Biology of the Placenta

Part of the Current Clinical Pathology book series (CCPATH)


The placenta is a transient organ consisting of cell types that are unique to eutherian mammals. It is fetal in origin and shares just half of the genome with that of the maternal uterus. Although existing for only 9 months, there are constant morphological and biological fluctuations within the placenta proper and at the interface between the placenta and the maternal endomyometrium. It is at the latter interface that unique fetomaternal tissue remodeling, hormonal regulation, and immunological interactions are regulated in such a delicate balance, so that appropriate maternal support can be delivered to the embryo and the mother does not illicit an immunologic rejection response to the growing gestational structures. Proliferative disorders including tumors arising from the placenta have distinct genetic, biological, and immunological properties that are drastically different from those of the maternal neoplasms. Recent findings of genomic imprinting including imprinted X chromosome inactivation in the placenta and its implication in the pathogenesis of gestational trophoblastic diseases raised some fundamental questions in mammalian biology and oncology.


Placental development Implantation Trophoblastic cells Genomic imprinting and placental evolution 


  1. 1.
    Aplin JD. The cell biology of human implantation. Placenta. 1996;17(5–6):269–75.PubMedGoogle Scholar
  2. 2.
    Fox H. Pathology of the placenta. Clin Obstet Gynaecol. 1986;13(3):501–19.PubMedGoogle Scholar
  3. 3.
    Carson DD, Bagchi I, Dey SK, Enders AC, Fazleabas AT, Lessey BA, et al. Embryo implantation. Dev Biol. 2000;223(2):217–37.PubMedGoogle Scholar
  4. 4.
    Bagchi IC, Li Q, Cheon YP. Role of steroid ­hormone-regulated genes in implantation. Ann N Y Acad Sci. 2001;943:68–76.PubMedGoogle Scholar
  5. 5.
    Cheng JG, Rodriguez CI, Stewart CL. Control of uterine receptivity and embryo implantation by steroid hormone regulation of LIF production and LIF receptor activity: towards a molecular understanding of “the window of implantation”. Rev Endocr Metab Disord. 2002;3(2):119–26.PubMedGoogle Scholar
  6. 6.
    Momoeda M, Taketani Y, Mizuno M, Iwamori M, Nagai Y. Characteristic expression of cholesterol sulfate in rabbit endometrium during the implantation period. Biochem Biophys Res Commun. 1991;178(1):145–50.PubMedGoogle Scholar
  7. 7.
    Abulencia A, Acosta D, Adelman J, Affolder T, Akimoto T, Albrow MG, et al. Measurement of the tt production cross section in pp collisions at square root of s = 1.96 TeV. Phys Rev Lett. 2006;97(8):082004.PubMedGoogle Scholar
  8. 8.
    Nardo LG, Nikas G, Makrigiannakis A. Molecules in blastocyst implantation. Role of matrix metalloproteinases, cytokines and growth factors. J Reprod Med. 2003;48(3):137–47.PubMedGoogle Scholar
  9. 9.
    Wang J, Mayernik L, Armant DR. Trophoblast adhesion of the peri-implantation mouse blastocyst is regulated by integrin signaling that targets phospholipase C. Dev Biol. 2007;302(1):143–53.PubMedGoogle Scholar
  10. 10.
    Shimomura Y, Ando H, Furugori K, Kajiyama H, Suzuki M, Iwase A, et al. Possible involvement of crosstalk cell-adhesion mechanism by endometrial CD26/dipeptidyl peptidase IV and embryonal fibronectin in human blastocyst implantation. Mol Hum Reprod. 2006;12(8):491–5.PubMedGoogle Scholar
  11. 11.
    Kimber SJ. Molecular interactions at the maternal-embryonic interface during the early phase of implantation. Semin Reprod Med. 2000;18(3):237–53.PubMedGoogle Scholar
  12. 12.
    Charles D. The Arias Stella reaction. J Obstet Gynaecol Br Emp. 1962;69:1006–10.PubMedGoogle Scholar
  13. 13.
    Arias-Stella J. The Arias-Stella reaction: facts and fancies four decades after. Adv Anat Pathol. 2002;9(1):12–23.PubMedGoogle Scholar
  14. 14.
    Achen MG, Gad JM, Stacker SA, Wilks AF. Placenta growth factor and vascular endothelial growth factor are co-expressed during early embryonic development. Growth Factors. 1997;15(1):69–80.PubMedGoogle Scholar
  15. 15.
    Cross JC, Werb Z, Fisher SJ. Implantation and the placenta: key pieces of the development puzzle. Science. 1994;266(5190):1508–18.PubMedGoogle Scholar
  16. 16.
    Damsky CH, Fitzgerald ML, Fisher SJ. Distribution patterns of extracellular matrix components and adhesion receptors are intricately modulated during first trimester cytotrophoblast differentiation along the invasive pathway, in vivo. J Clin Invest. 1992;89(1):210–22.PubMedGoogle Scholar
  17. 17.
    Simon C, Moreno C, Remohi J, Pellicer A. Molecular interactions between embryo and uterus in the adhesion phase of human implantation. Hum Reprod. 1998;13 Suppl 3:219–32. discussion 33-6.PubMedGoogle Scholar
  18. 18.
    Kimber SJ, Spanswick C. Blastocyst implantation: the adhesion cascade. Semin Cell Dev Biol. 2000;11(2):77–92.PubMedGoogle Scholar
  19. 19.
    Yoshinaga K. Research on blastocyst implantation essential factors (BIEFs). Am J Reprod Immunol. 2010;63(6):413–24.PubMedGoogle Scholar
  20. 20.
    Carlson BM. Human Embryology and Developmental Biology. St.Louis: Mosby; 1994.Google Scholar
  21. 21.
    Enders AC, Schlafke S. Cytological aspects of trophoblast-uterine interaction in early implantation. Am J Anat. 1969;125(1):1–29.PubMedGoogle Scholar
  22. 22.
    Yasumasu S, Kawaguchi M, Ouchi S, Sano K, Murata K, Sugiyama H, et al. Mechanism of egg envelope digestion by hatching enzymes, HCE and LCE in medaka, Oryzias latipes. J Biochem. 2010;148(4):439–48.PubMedGoogle Scholar
  23. 23.
    Cannon MJ, Menino Jr AR. Changes in the bovine zona pellucida induced by plasmin or embryonic plasminogen activator. Mol Reprod Dev. 1998;51(3):330–8.PubMedGoogle Scholar
  24. 24.
    Quesada V, Sanchez LM, Alvarez J, Lopez-Otin C. Identification and characterization of human and mouse ovastacin: a novel metalloproteinase similar to hatching enzymes from arthropods, birds, amphibians, and fish. J Biol Chem. 2004;279(25):26627–34.PubMedGoogle Scholar
  25. 25.
    O’Sullivan CM, Liu SY, Karpinka JB, Rancourt DE. Embryonic hatching enzyme strypsin/ISP1 is expressed with ISP2 in endometrial glands during implantation. Mol Reprod Dev. 2002;62(3):328–34.PubMedGoogle Scholar
  26. 26.
    Sharma N, Liu S, Tang L, Irwin J, Meng G, Rancourt DE. Implantation Serine Proteinases heterodimerize and are critical in hatching and implantation. BMC Dev Biol. 2006;6:61.PubMedGoogle Scholar
  27. 27.
    Coates AA, Menino Jr AR. Effects of blastocoelic expansion and plasminogen activator activity on hatching and zona pellucida solubility in bovine embryos in vitro. J Anim Sci. 1994;72(11):2936–42.PubMedGoogle Scholar
  28. 28.
    Wu TC, Wan YJ, Damjanov I. Positioning of inner cell mass determines the development of mouse blastocysts in vitro. J Embryol Exp Morphol. 1981;65:105–17.PubMedGoogle Scholar
  29. 29.
    Copp AJ. Interaction between inner cell mass and trophectoderm of the mouse blastocyst. II. The fate of the polar trophectoderm. J Embryol Exp Morphol. 1979;51:109–20.PubMedGoogle Scholar
  30. 30.
    Jones CJ, Fazleabas AT. Ultrastructure of epithelial plaque formation and stromal cell transformation by post-ovulatory chorionic gonadotrophin treatment in the baboon (Papio anubis). Hum Reprod. 2001;16(12):2680–90.PubMedGoogle Scholar
  31. 31.
    Zygmunt M, Hahn D, Munstedt K, Bischof P, Lang U. Invasion of cytotrophoblastic JEG-3 cells is stimulated by hCG in vitro. Placenta. 1998;19(8):587–93.PubMedGoogle Scholar
  32. 32.
    Wilcox AJ, Baird DD, Weinberg CR. Time of implantation of the conceptus and loss of pregnancy. N Engl J Med. 1999;340(23):1796–9.PubMedGoogle Scholar
  33. 33.
    Edwards RG. Human uterine endocrinology and the implantation window. Ann N Y Acad Sci. 1988;541:445–54.PubMedGoogle Scholar
  34. 34.
    Grewal S, Carver JG, Ridley AJ, Mardon HJ. Implantation of the human embryo requires Rac1-dependent endometrial stromal cell migration. Proc Natl Acad Sci USA. 2008;105(42):16189–94.PubMedGoogle Scholar
  35. 35.
    Qin J, Diaz-Cueto L, Schwarze JE, Takahashi Y, Imai M, Isuzugawa K, et al. Effects of progranulin on blastocyst hatching and subsequent adhesion and outgrowth in the mouse. Biol Reprod. 2005;73(3):434–42.PubMedGoogle Scholar
  36. 36.
    Matsumoto H, Daikoku T, Wang H, Sato E, Dey SK. Differential expression of ezrin/radixin/moesin (ERM) and ERM-associated adhesion molecules in the blastocyst and uterus suggests their functions during implantation. Biol Reprod. 2004;70(3):729–36.PubMedGoogle Scholar
  37. 37.
    Nagaoka K, Nojima H, Watanabe F, Chang KT, Christenson RK, Sakai S, et al. Regulation of blastocyst migration, apposition, and initial adhesion by a chemokine, interferon gamma-inducible protein 10 kDa (IP-10), during early gestation. J Biol Chem. 2003;278(31):29048–56.PubMedGoogle Scholar
  38. 38.
    Robson P, Stein P, Zhou B, Schultz RM, Baldwin HS. Inner cell mass-specific expression of a cell adhesion molecule (PECAM-1/CD31) in the mouse blastocyst. Dev Biol. 2001;234(2):317–29.PubMedGoogle Scholar
  39. 39.
    Galan A, O’Connor JE, Valbuena D, Herrer R, Remohi J, Pampfer S, et al. The human blastocyst regulates endometrial epithelial apoptosis in embryonic adhesion. Biol Reprod. 2000;63(2):430–9.PubMedGoogle Scholar
  40. 40.
    Grewal S, Carver J, Ridley AJ, Mardon HJ. Human endometrial stromal cell rho GTPases have opposing roles in regulating focal adhesion turnover and embryo invasion in vitro. Biol Reprod. 2010;83(1):75–82.PubMedGoogle Scholar
  41. 41.
    Carson DD, DeSouza MM, Regisford EG. Mucin and proteoglycan functions in embryo implantation. Bioessays. 1998;20(7):577–83.PubMedGoogle Scholar
  42. 42.
    Smith SE, French MM, Julian J, Paria BC, Dey SK, Carson DD. Expression of heparan sulfate proteoglycan (perlecan) in the mouse blastocyst is regulated during normal and delayed implantation. Dev Biol. 1997;184(1):38–47.PubMedGoogle Scholar
  43. 43.
    Carson DD, Tang JP, Julian J. Heparan sulfate proteoglycan (perlecan) expression by mouse embryos during acquisition of attachment competence. Dev Biol. 1993;155(1):97–106.PubMedGoogle Scholar
  44. 44.
    Lessey BA, Castelbaum AJ, Sawin SW, Sun J. Integrins as markers of uterine receptivity in women with primary unexplained infertility. Fertil Steril. 1995;63(3):535–42.PubMedGoogle Scholar
  45. 45.
    Genbacev OD, Prakobphol A, Foulk RA, Krtolica AR, Ilic D, Singer MS, et al. Trophoblast L-selectin-mediated adhesion at the maternal-fetal interface. Science. 2003;299(5605):405–8.PubMedGoogle Scholar
  46. 46.
    Lobo SC, Huang ST, Germeyer A, Dosiou C, Vo KC, Tulac S, et al. The immune environment in human endometrium during the window of implantation. Am J Reprod Immunol. 2004;52(4):244–51.PubMedGoogle Scholar
  47. 47.
    Pijnenborg R, Robertson WB, Brosens I, Dixon G. Review article: trophoblast invasion and the establishment of haemochorial placentation in man and laboratory animals. Placenta. 1981;2(1):71–91.PubMedGoogle Scholar
  48. 48.
    Genbacev O, Joslin R, Damsky CH, Polliotti BM, Fisher SJ. Hypoxia alters early gestation human cytotrophoblast differentiation/invasion in vitro and models the placental defects that occur in preeclampsia. J Clin Invest. 1996;97(2):540–50.PubMedGoogle Scholar
  49. 49.
    Genbacev O, Zhou Y, Ludlow JW, Fisher SJ. Regulation of human placental development by oxygen tension. Science. 1997;277(5332):1669–72.PubMedGoogle Scholar
  50. 50.
    Gobble RM, Groesch KA, Chang M, Torry RJ, Torry DS. Differential regulation of human PlGF gene expression in trophoblast and nontrophoblast cells by oxygen tension. Placenta. 2009;30(10):869–75.PubMedGoogle Scholar
  51. 51.
    Hurskainen T, Seiki M, Apte SS, Syrjakallio-Ylitalo M, Sorsa T, Oikarinen A, et al. Production of membrane-type matrix metalloproteinase-1 (MT-MMP-1) in early human placenta. A possible role in placental implantation? J Histochem Cytochem. 1998;46(2):221–9.PubMedGoogle Scholar
  52. 52.
    Liu G, Zhang X, Lin H, Wang H, Li Q, Ni J, et al. Effects of E-cadherin on mouse embryo implantation and expression of matrix metalloproteinase-2 and -9. Biochem Biophys Res Commun. 2006;343(3):832–8.PubMedGoogle Scholar
  53. 53.
    Gao F, Chen XL, Wei P, Gao HJ, Liu YX. Expression of matrix metalloproteinase-2, tissue inhibitors of metalloproteinase-1, -3 at the implantation site of rhesus monkey during the early stage of pregnancy. Endocrine. 2001;16(1):47–54.PubMedGoogle Scholar
  54. 54.
    Li L, Chen S, Xing F. Expression of matrix metalloproteinase-9 and tissue inhibitor of metalloproteinase-3 protein in the implantation window phase of endometrium. Zhonghua Fu Chan Ke Za Zhi. 2000;35(9):544–6.PubMedGoogle Scholar
  55. 55.
    Raga F, Casan EM, Wen Y, Huang HY, Bonilla-Musoles F, Polan ML. Independent regulation of matrix metalloproteinase-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and TIMP-3 in human endometrial stromal cells by gonadotropin-releasing hormone: implications in early human implantation. J Clin Endocrinol Metab. 1999;84(2):636–42.PubMedGoogle Scholar
  56. 56.
    Irwin JC, Suen LF, Faessen GH, Popovici RM, Giudice LC. Insulin-like growth factor (IGF)-II inhibition of endometrial stromal cell tissue inhibitor of metalloproteinase-3 and IGF-binding protein-1 suggests paracrine interactions at the decidua:trophoblast interface during human implantation. J Clin Endocrinol Metab. 2001;86(5):2060–4.PubMedGoogle Scholar
  57. 57.
    Klemke RL, Cai S, Giannini AL, Gallagher PJ, de Lanerolle P, Cheresh DA. Regulation of cell motility by mitogen-activated protein kinase. J Cell Biol. 1997;137(2):481–92.PubMedGoogle Scholar
  58. 58.
    McKinnon T, Chakraborty C, Gleeson LM, Chidiac P, Lala PK. Stimulation of human extravillous trophoblast migration by IGF-II is mediated by IGF type 2 receptor involving inhibitory G protein(s) and phosphorylation of MAPK. J Clin Endocrinol Metab. 2001;86(8):3665–74.PubMedGoogle Scholar
  59. 59.
    Gleeson LM, Chakraborty C, McKinnon T, Lala PK. Insulin-like growth factor-binding protein 1 stimulates human trophoblast migration by signaling through alpha 5 beta 1 integrin via mitogen-activated protein Kinase pathway. J Clin Endocrinol Metab. 2001;86(6):2484–93.PubMedGoogle Scholar
  60. 60.
    Shih I, Wang T, Wu T, Kurman RJ, Gearhart JD. Expression of Mel-CAM in implantation site intermediate trophoblastic cell line, IST-1, limits its migration on uterine smooth muscle cells. J Cell Sci. 1998;111(Pt 17):2655–64.PubMedGoogle Scholar
  61. 61.
    Graham CH, Lala PK. Mechanisms of placental invasion of the uterus and their control. Biochem Cell Biol. 1992;70(10–11):867–74.PubMedGoogle Scholar
  62. 62.
    Busch S, Renaud SJ, Schleussner E, Graham CH, Markert UR. mTOR mediates human trophoblast invasion through regulation of matrix-remodeling enzymes and is associated with serine phosphorylation of STAT3. Exp Cell Res. 2009;315(10):1724–33.PubMedGoogle Scholar
  63. 63.
    Kovats S, Main EK, Librach C, Stubblebine M, Fisher SJ, DeMars R. A class I antigen, HLA-G, expressed in human trophoblasts. Science. 1990;248(4952):220–3.PubMedGoogle Scholar
  64. 64.
    McMaster MT, Librach CL, Zhou Y, Lim KH, Janatpour MJ, DeMars R, et al. Human placental HLA-G expression is restricted to differentiated cytotrophoblasts. J Immunol. 1995;154(8):3771–8.PubMedGoogle Scholar
  65. 65.
    Bondarenko GI, Burleigh DW, Durning M, Breburda EE, Grendell RL, Golos TG. Passive immunization against the MHC class I molecule Mamu-AG disrupts rhesus placental development and endometrial responses. J Immunol. 2007;179(12):8042–50.PubMedGoogle Scholar
  66. 66.
    Hess AP, Hamilton AE, Talbi S, Dosiou C, Nyegaard M, Nayak N, et al. Decidual stromal cell response to paracrine signals from the trophoblast: amplification of immune and angiogenic modulators. Biol Reprod. 2007;76(1):102–17.PubMedGoogle Scholar
  67. 67.
    Arimoto-Ishida E, Sakata M, Sawada K, Nakayama M, Nishimoto F, Mabuchi S, et al. Up-regulation of alpha5-integrin by E-cadherin loss in hypoxia and its key role in the migration of extravillous trophoblast cells during early implantation. Endocrinology. 2009;150(9):4306–15.PubMedGoogle Scholar
  68. 68.
    Li Q, Wang J, Armant DR, Bagchi MK, Bagchi IC. Calcitonin down-regulates E-cadherin expression in rodent uterine epithelium during implantation. J Biol Chem. 2002;277(48):46447–55.PubMedGoogle Scholar
  69. 69.
    Shih Ie M, Hsu MY, Oldt 3rd RJ, Herlyn M, Gearhart JD, Kurman RJ. The role of E-cadherin in the motility and invasion of implantation site intermediate trophoblast. Placenta. 2002;23(10):706–15.PubMedGoogle Scholar
  70. 70.
    Bulla R, Villa A, Bossi F, Cassetti A, Radillo O, Spessotto P, et al. VE-cadherin is a critical molecule for trophoblast-endothelial cell interaction in decidual spiral arteries. Exp Cell Res. 2005;303(1):101–13.PubMedGoogle Scholar
  71. 71.
    Garcia P, Nieto A, Sanchez MA, Pizarro M, Flores JM. Expression of alphav, alpha4, alpha5 and beta3 integrin subunits, fibronectin and vitronectin in goat peri-implantation. Anim Reprod Sci. 2004;80(1–2):91–100.PubMedGoogle Scholar
  72. 72.
    Ruan HC, Huang HF, Jin F. The expression of integrin beta3 in mice’s endometrium during the implantation window based on different ovarian stimulation protocols. Zhonghua Yi Xue Za Zhi. 2004;84(10):857–60.PubMedGoogle Scholar
  73. 73.
    von Wolff M, Strowitzki T, Becker V, Zepf C, Tabibzadeh S, Thaler CJ. Endometrial osteopontin, a ligand of beta3-integrin, is maximally expressed around the time of the “implantation window”. Fertil Steril. 2001;76(4):775–81.Google Scholar
  74. 74.
    Saito S, Nakashima A, Myojo-Higuma S, Shiozaki A. The balance between cytotoxic NK cells and regulatory NK cells in human pregnancy. J Reprod Immunol. 2008;77(1):14–22.PubMedGoogle Scholar
  75. 75.
    Saito S, Shiozaki A, Sasaki Y, Nakashima A, Shima T, Ito M. Regulatory T cells and regulatory natural killer (NK) cells play important roles in feto-maternal tolerance. Semin Immunopathol. 2007;29(2):115–22.PubMedGoogle Scholar
  76. 76.
    King A, Allan DS, Bowen M, Powis SJ, Joseph S, Verma S, et al. HLA-E is expressed on trophoblast and interacts with CD94/NKG2 receptors on decidual NK cells. Eur J Immunol. 2000;30(6):1623–31.PubMedGoogle Scholar
  77. 77.
    Shih IM, Kurman RJ. New concepts in trophoblastic growth and differentiation with practical application for the diagnosis of gestational trophoblastic disease. Verh Dtsch Ges Pathol. 1997;81:266–72.PubMedGoogle Scholar
  78. 78.
    Shih Ie M. Gestational trophoblastic tumors and related tumor-like lesions. In: Kurman R, editor. Blaustein’s Pathology of the Female Genital Tract. 6th ed. New York: Springer; 2010.Google Scholar
  79. 79.
    Mi S, Lee X, Li X, Veldman GM, Finnerty H, Racie L, et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature. 2000;403(6771):785–9.PubMedGoogle Scholar
  80. 80.
    Shih IM, Kurman RJ. The pathology of intermediate trophoblastic tumors and tumor-like lesions. Int J Gynecol Pathol. 2001;20(1):31–47.PubMedGoogle Scholar
  81. 81.
    Yeh IT, O’Connor DM, Kurman RJ. Vacuolated cytotrophoblast: a subpopulation of trophoblast in the chorion laeve. Placenta. 1989;10(5):429–38.PubMedGoogle Scholar
  82. 82.
    Wan SK, Lam PW, Pau MY, Chan JK. Multiclefted nuclei. A helpful feature for identification of intermediate trophoblastic cells in uterine curetting specimens. Am J Surg Pathol. 1992;16(12):1226–32.PubMedGoogle Scholar
  83. 83.
    Shih Ie M. Trophogram, an immunohistochemistry-based algorithmic approach, in the differential diagnosis of trophoblastic tumors and tumorlike lesions. Ann Diagn Pathol. 2007;11(3):228–34.PubMedGoogle Scholar
  84. 84.
    Mao TL, Seidman JD, Kurman RJ, Shih Ie M. Cyclin E and p16 immunoreactivity in epithelioid trophoblastic tumor–an aid in differential diagnosis. Am J Surg Pathol. 2006;30(9):1105–10.PubMedGoogle Scholar
  85. 85.
    Shih IM, Kurman RJ. Ki-67 labeling index in the differential diagnosis of exaggerated placental site, placental site trophoblastic tumor, and choriocarcinoma: a double immunohistochemical staining technique using Ki-67 and Mel-CAM antibodies. Hum Pathol. 1998;29(1):27–33.PubMedGoogle Scholar
  86. 86.
    Ferguson-Smith AC, Surani MA. Imprinting and the epigenetic asymmetry between parental genomes. Science. 2001;293(5532):1086–9.PubMedGoogle Scholar
  87. 87.
    Coan PM, Burton GJ, Ferguson-Smith AC. Imprinted genes in the placenta–a review. Placenta. 2005;26(Suppl A):S10–20.PubMedGoogle Scholar
  88. 88.
    Morison IM, Ramsay JP, Spencer HG. A census of mammalian imprinting. Trends Genet. 2005;21(8):457–65.PubMedGoogle Scholar
  89. 89.
    Reik W, Lewis A. Co-evolution of X-chromosome inactivation and imprinting in mammals. Nat Rev Genet. 2005;6(5):403–10.PubMedGoogle Scholar
  90. 90.
    Frost JM, Moore GE. The importance of imprinting in the human placenta. PLoS Genet. 2010;6:e1001015.PubMedGoogle Scholar
  91. 91.
    Caspary T, Cleary MA, Baker CC, Guan XJ, Tilghman SM. Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster. Mol Cell Biol. 1998;18(6):3466–74.PubMedGoogle Scholar
  92. 92.
    Zwart R, Sleutels F, Wutz A, Schinkel AH, Barlow DP. Bidirectional action of the Igf2r imprint control element on upstream and downstream imprinted genes. Genes Dev. 2001;15(18):2361–6.PubMedGoogle Scholar
  93. 93.
    Higashimoto K, Soejima H, Yatsuki H, Joh K, Uchiyama M, Obata Y, et al. Characterization and imprinting status of OBPH1/Obph1 gene: implications for an extended imprinting domain in human and mouse. Genomics. 2002;80(6):575–84.PubMedGoogle Scholar
  94. 94.
    Mizuno Y, Sotomaru Y, Katsuzawa Y, Kono T, Meguro M, Oshimura M, et al. Asb4, Ata3, and Dcn are novel imprinted genes identified by high-throughput screening using RIKEN cDNA microarray. Biochem Biophys Res Commun. 2002;290(5):1499–505.PubMedGoogle Scholar
  95. 95.
    Ono R, Shiura H, Aburatani H, Kohda T, Kaneko-Ishino T, Ishino F. Identification of a large novel imprinted gene cluster on mouse proximal chromosome 6. Genome Res. 2003;13(7):1696–705.PubMedGoogle Scholar
  96. 96.
    Sandell LL, Guan XJ, Ingram R, Tilghman SM. Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta. Proc Natl Acad Sci USA. 2003;100(8):4622–7.PubMedGoogle Scholar
  97. 97.
    Ono R, Nakamura K, Inoue K, Naruse M, Usami T, Wakisaka-Saito N, et al. Deletion of Peg10, an imprinted gene acquired from a retrotransposon, causes early embryonic lethality. Nat Genet. 2006;38(1):101–6.PubMedGoogle Scholar
  98. 98.
    Hedges SB. The origin and evolution of model organisms. Nat Rev Genet. 2002;3(11):838–49.PubMedGoogle Scholar
  99. 99.
    Kaneko-Ishino T, Ishino F. Retrotransposon silencing by DNA methylation contributed to the evolution of placentation and genomic imprinting in mammals. Dev Growth Differ. 2010;52(6):533–43.PubMedGoogle Scholar
  100. 100.
    Tycko B, Efstratiadis A. Genomic imprinting: piece of cake. Nature. 2002;417(6892):913–4.PubMedGoogle Scholar
  101. 101.
    Tycko B, Morison IM. Physiological functions of imprinted genes. J Cell Physiol. 2002;192(3):245–58.PubMedGoogle Scholar
  102. 102.
    Feil R, Berger F. Convergent evolution of genomic imprinting in plants and mammals. Trends Genet. 2007;23(4):192–9.PubMedGoogle Scholar
  103. 103.
    Salas M, John R, Saxena A, Barton S, Frank D, Fitzpatrick G, et al. Placental growth retardation due to loss of imprinting of Phlda2. Mech Dev. 2004;121(10):1199–210.PubMedGoogle Scholar
  104. 104.
    Takahashi K, Kobayashi T, Kanayama N. p57(Kip2) regulates the proper development of labyrinthine and spongiotrophoblasts. Mol Hum Reprod. 2000;6(11):1019–25.PubMedGoogle Scholar
  105. 105.
    Oudejans CB, Mulders J, Lachmeijer AM, van Dijk M, Konst AA, Westerman BA, et al. The parent-of-origin effect of 10q22 in pre-eclamptic females coincides with two regions clustered for genes with down-regulated expression in androgenetic placentas. Mol Hum Reprod. 2004;10(8):589–98.PubMedGoogle Scholar
  106. 106.
    van Dijk M, Mulders J, Konst A, Janssens B, van Roy F, Blankenstein M, et al. Differential downregulation of alphaT-catenin expression in placenta: trophoblast cell type-dependent imprinting of the CTNNA3 gene. Gene Expr Patterns. 2004;5(1):61–5.PubMedGoogle Scholar
  107. 107.
    Noguer-Dance M, Abu-Amero S, Al-Khtib M, Lefevre A, Coullin P, Moore GE, et al. The primate-specific microRNA gene cluster (C19MC) is imprinted in the placenta. Hum Mol Genet. 2010;19(18):3566–82.PubMedGoogle Scholar
  108. 108.
    Lewis A, Mitsuya K, Umlauf D, Smith P, Dean W, Walter J, et al. Imprinting on distal chromosome 7 in the placenta involves repressive histone methylation independent of DNA methylation. Nat Genet. 2004;36(12):1291–5.PubMedGoogle Scholar
  109. 109.
    Mager J, Montgomery ND, de Villena FP, Magnuson T. Genome imprinting regulated by the mouse Polycomb group protein Eed. Nat Genet. 2003;33(4):502–7.PubMedGoogle Scholar
  110. 110.
    Silva J, Mak W, Zvetkova I, Appanah R, Nesterova TB, Webster Z, et al. Establishment of histone h3 methylation on the inactive X chromosome requires transient recruitment of Eed-Enx1 polycomb group complexes. Dev Cell. 2003;4(4):481–95.PubMedGoogle Scholar
  111. 111.
    Cao R, Zhang Y. The functions of E(Z)/EZH2-mediated methylation of lysine 27 in histone H3. Curr Opin Genet Dev. 2004;14(2):155–64.PubMedGoogle Scholar
  112. 112.
    Umlauf D, Goto Y, Cao R, Cerqueira F, Wagschal A, Zhang Y, et al. Imprinting along the Kcnq1 domain on mouse chromosome 7 involves repressive histone methylation and recruitment of Polycomb group complexes. Nat Genet. 2004;36(12):1296–300.PubMedGoogle Scholar
  113. 113.
    Montgomery ND, Yee D, Chen A, Kalantry S, Chamberlain SJ, Otte AP, et al. The murine ­polycomb group protein Eed is required for global histone H3 lysine-27 methylation. Curr Biol. 2005;15(10):942–7.PubMedGoogle Scholar
  114. 114.
    Cooper DW, VandeBerg JL, Sharman GB, Poole WE. Phosphoglycerate kinase polymorphism in kangaroos provides further evidence for paternal X inactivation. Nat New Biol. 1971;230(13):155–7.PubMedGoogle Scholar
  115. 115.
    Graves JA. Review: sex chromosome evolution and the expression of sex-specific genes in the placenta. Placenta. 2010;31(Suppl):S27–32.PubMedGoogle Scholar
  116. 116.
    Wagschal A, Feil R. Genomic imprinting in the placenta. Cytogenet Genome Res. 2006;113(1–4):90–8.PubMedGoogle Scholar
  117. 117.
    Hemberger M. Epigenetic landscape required for placental development. Cell Mol Life Sci. 2007;64(18):2422–36.PubMedGoogle Scholar
  118. 118.
    Mak W, Nesterova TB, de Napoles M, Appanah R, Yamanaka S, Otte AP, et al. Reactivation of the paternal X chromosome in early mouse embryos. Science. 2004;303(5658):666–9.PubMedGoogle Scholar
  119. 119.
    Okamoto I, Otte AP, Allis CD, Reinberg D, Heard E. Epigenetic dynamics of imprinted X inactivation during early mouse development. Science. 2004;303(5658):644–9.PubMedGoogle Scholar
  120. 120.
    Sado T, Fenner MH, Tan SS, Tam P, Shioda T, Li E. X inactivation in the mouse embryo deficient for Dnmt1: distinct effect of hypomethylation on imprinted and random X inactivation. Dev Biol. 2000;225(2):294–303.PubMedGoogle Scholar
  121. 121.
    Avner P, Heard E. X-chromosome inactivation: counting, choice and initiation. Nat Rev Genet. 2001;2(1):59–67.PubMedGoogle Scholar
  122. 122.
    Brockdorff N. X-chromosome inactivation: closing in on proteins that bind Xist RNA. Trends Genet. 2002;18(7):352–8.PubMedGoogle Scholar
  123. 123.
    Li E, Beard C, Forster AC, Bestor TH, Jaenisch R. DNA methylation, genomic imprinting, and mammalian development. Cold Spring Harb Symp Quant Biol. 1993;58:297–305.PubMedGoogle Scholar
  124. 124.
    Lee JT. Molecular links between X-inactivation and autosomal imprinting: X-inactivation as a driving force for the evolution of imprinting? Curr Biol. 2003;13(6):R242–54.PubMedGoogle Scholar
  125. 125.
    Reik W, Ferguson-Smith AC. Developmental biology: the X-inactivation yo-yo. Nature. 2005;438(7066):297–8.PubMedGoogle Scholar
  126. 126.
    Li Y, Lemaire P, Behringer RR. Esx1, a novel X chromosome-linked homeobox gene expressed in mouse extraembryonic tissues and male germ cells. Dev Biol. 1997;188(1):85–95.PubMedGoogle Scholar
  127. 127.
    Lin TP, Labosky PA, Grabel LB, Kozak CA, Pitman JL, Kleeman J, et al. The Pem homeobox gene is X-linked and exclusively expressed in extraembryonic tissues during early murine development. Dev Biol. 1994;166(1):170–9.PubMedGoogle Scholar
  128. 128.
    Huynh KD, Lee JT. Inheritance of a pre-inactivated paternal X chromosome in early mouse embryos. Nature. 2003;426(6968):857–62.PubMedGoogle Scholar
  129. 129.
    Sado T, Ferguson-Smith AC. Imprinted X inactivation and reprogramming in the preimplantation mouse embryo. Hum Mol Genet. 2005;14(Spec No 1):R59–64.PubMedGoogle Scholar
  130. 130.
    Migeon BR, Do TT. In search of nonrandom X inactivation: studies of the placenta from newborns heterozygous for glucose-6-phosphate dehydrogenase. Basic Life Sci. 1978;12:379–91.PubMedGoogle Scholar
  131. 131.
    Looijenga LH, Gillis AJ, Verkerk AJ, van Putten WL, Oosterhuis JW. Heterogeneous X inactivation in trophoblastic cells of human full-term female placentas. Am J Hum Genet. 1999;64(5):1445–52.PubMedGoogle Scholar
  132. 132.
    Lee JT. Is X-chromosome inactivation a homology effect? Adv Genet. 2002;46:25–48.PubMedGoogle Scholar
  133. 133.
    Moreira de Mello JC, de Araujo ES, Stebellini R, Fraga AM, de Souza JE, Sumita DR, et al. Random X inactivation and extensive mosaicism in human placental revealed by analysis of allele-specific gene expression along the X chromosome. PLoS One. 2010;5(6):e10947.PubMedGoogle Scholar
  134. 134.
    Ropers HH, Wolff G, Hitzeroth HW. Preferential X inactivation in human placenta membranes: is the paternal X inactive in early embryonic development of female mammals? Hum Genet. 1978;43(3):265–73.PubMedGoogle Scholar
  135. 135.
    Harrison KB, Warburton D. Preferential X-chromosome activity in human female placental tissues. Cytogenet Cell Genet. 1986;41(3):163–8.PubMedGoogle Scholar
  136. 136.
    Goto T, Wright E, Monk M. Paternal X-chromosome inactivation in human trophoblastic cells. Mol Hum Reprod. 1997;3(1):77–80.PubMedGoogle Scholar
  137. 137.
    Uehara S, Tamura M, Nata M, Ji G, Yaegashi N, Okamura K, et al. X-chromosome inactivation in the human trophoblast of early pregnancy. J Hum Genet. 2000;45(3):119–26.PubMedGoogle Scholar
  138. 138.
    Migeon BR, Axelman J, Jeppesen P. Differential X reactivation in human placental cells: implications for reversal of X inactivation. Am J Hum Genet. 2005;77(3):355–64.PubMedGoogle Scholar
  139. 139.
    Haig D, Graham C. Genomic imprinting and the strange case of the insulin-like growth factor II receptor. Cell. 1991;64(6):1045–6.PubMedGoogle Scholar
  140. 140.
    Moore T, Haig D. Genomic imprinting in mammalian development: a parental tug-of-war. Trends Genet. 1991;7(2):45–9.PubMedGoogle Scholar
  141. 141.
    Haig D, Westoby M. An earlier formulation of the genetic conflict hypothesis of genomic imprinting. Nat Genet. 2006;38(3):271.PubMedGoogle Scholar
  142. 142.
    Solter D. Imprinting. Int J Dev Biol. 1998;42(7):951–4.PubMedGoogle Scholar
  143. 143.
    Abu-Amero S, Monk D, Apostolidou S, Stanier P, Moore G. Imprinted genes and their role in human fetal growth. Cytogenet Genome Res. 2006;113(1–4):262–70.PubMedGoogle Scholar
  144. 144.
    Barlow DP. Gametic imprinting in mammals. Science. 1995;270(5242):1610–3.PubMedGoogle Scholar
  145. 145.
    Tilghman SM. The sins of the fathers and mothers: genomic imprinting in mammalian development. Cell. 1999;96(2):185–93.PubMedGoogle Scholar
  146. 146.
    Constancia M, Kelsey G, Reik W. Resourceful imprinting. Nature. 2004;432(7013):53–7.PubMedGoogle Scholar
  147. 147.
    McGrath J, Solter D. Completion of mouse embryogenesis requires both the maternal and paternal genomes. Cell. 1984;37(1):179–83.PubMedGoogle Scholar
  148. 148.
    Surani MA, Barton SC, Norris ML. Development of reconstituted mouse eggs suggests imprinting of the genome during gametogenesis. Nature. 1984;308(5959):548–50.PubMedGoogle Scholar
  149. 149.
    Ferguson-Smith AC, Cattanach BM, Barton SC, Beechey CV, Surani MA. Embryological and molecular investigations of parental imprinting on mouse chromosome 7. Nature. 1991;351(6328):667–70.PubMedGoogle Scholar
  150. 150.
    Leighton PA, Ingram RS, Eggenschwiler J, Efstratiadis A, Tilghman SM. Disruption of imprinting caused by deletion of the H19 gene region in mice. Nature. 1995;375(6526):34–9.PubMedGoogle Scholar
  151. 151.
    Gicquel C, Rossignol S, Cabrol S, Houang M, Steunou V, Barbu V, et al. Epimutation of the ­telomeric imprinting center region on chromosome 11p15 in Silver-Russell syndrome. Nat Genet. 2005;37(9):1003–7.PubMedGoogle Scholar
  152. 152.
    Ludwig T, Eggenschwiler J, Fisher P, D’Ercole AJ, Davenport ML, Efstratiadis A. Mouse mutants lacking the type 2 IGF receptor (IGF2R) are rescued from perinatal lethality in Igf2 and Igf1r null backgrounds. Dev Biol. 1996;177(2):517–35.PubMedGoogle Scholar
  153. 153.
    Frank D, Fortino W, Clark L, Musalo R, Wang W, Saxena A, et al. Placental overgrowth in mice ­lacking the imprinted gene Ipl. Proc Natl Acad Sci USA. 2002;99(11):7490–5.PubMedGoogle Scholar
  154. 154.
    Apostolidou S, Abu-Amero S, O’Donoghue K, Frost J, Olafsdottir O, Chavele KM, et al. Elevated placental expression of the imprinted PHLDA2 gene is associated with low birth weight. J Mol Med. 2007;85(4):379–87.PubMedGoogle Scholar
  155. 155.
    Castrillon DH, Sun D, Weremowicz S, Fisher RA, Crum CP, Genest DR. Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2. Am J Surg Pathol. 2001;25(10):1225–30.PubMedGoogle Scholar
  156. 156.
    Fukunaga M. Immunohistochemical characterization of p57(KIP2) expression in early hydatidiform moles. Hum Pathol. 2002;33(12):1188–92.PubMedGoogle Scholar
  157. 157.
    Monk D, Arnaud P, Frost J, Hills FA, Stanier P, Feil R, et al. Reciprocal imprinting of human GRB10 in placental trophoblast and brain: evolutionary conservation of reversed allelic expression. Hum Mol Genet. 2009;18(16):3066–74.PubMedGoogle Scholar
  158. 158.
    Charalambous M, Smith FM, Bennett WR, Crew TE, Mackenzie F, Ward A. Disruption of the imprinted Grb10 gene leads to disproportionate overgrowth by an Igf2-independent mechanism. Proc Natl Acad Sci USA. 2003;100(14):8292–7.PubMedGoogle Scholar
  159. 159.
    Charalambous M, Cowley M, Geoghegan F, Smith FM, Radford EJ, Marlow BP, et al. Maternally-inherited Grb10 reduces placental size and efficiency. Dev Biol. 2010;337(1):1–8.PubMedGoogle Scholar
  160. 160.
    Ou-Yang RJ, Hui P, Yang XJ, Zynger DL. Expression of glypican 3 in placental site trophoblastic tumor. Diagn Pathol. 2010;5:64.PubMedGoogle Scholar
  161. 161.
    Han VK, Bassett N, Walton J, Challis JR. The expression of insulin-like growth factor (IGF) and IGF-binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab. 1996;81(7):2680–93.PubMedGoogle Scholar
  162. 162.
    Shih I-M, Mazur MT, Kurman RJ. Gestational trophoblastic tumors and related tumor-like lesions. In: Kurman R, editor. Blaustein’s pathology of the female genital tract. 6th ed. New York: Springer; 2010.Google Scholar

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© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Department of PathologyYale University School of MedicineNew HavenUSA

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