Hsp90 in the Migration of Primordial Germ Cells: A Model to Study Long-Distance Cell Migration and Perhaps Cancer?

  • Marie Lejong
  • Nathalie Vanmuylder
  • Stéphane LouryanEmail author
Part of the Heat Shock Proteins book series (HESP, volume 19)


Primordial Germ Cells (PGC) are the progenitors of the germ-line and differentiate into spermatozoa or oocytes. They are responsible for the transmission of genetic and epigenetic information from one generation to the other. Since the nineteenth century, PGCs have been investigated using different techniques. Regardless of their mode of specification, inheritance or induction, PGCs arise early in development and migrate by a combination of passive and active movements towards the gonadic ridges. The migration of PGCs is very similar to the path taken by metastasis and germ cells are very often proposed as a model for the study of cell migration. Their pathway of migration is regulated by different signals that interact with Hsp90, an ATP-dependent chaperone associated with numerous tumors and used to grade the malignancy. Furthermore, some of the signals regulating PGCs have been proved to have a role in different cancers. This underlines the idea that PGCs could be an interesting tool to study long-distance cell migration and perhaps cancer.


Cancer Embryo Hsp90 Migration Primordial germ cell 



Actin related protein 2 homolog


Activin receptor-like kinase-2


Bone morphogenetic proteins


Bone morphogenetic protein receptor


Epithelial-mesenchymal transition


Gonadal ridge


Heat shock protein


Microtubule organizer center


Primordial germ cells


Rho-associated protein kinase


Transforming growth factor β



The authors thank Mrs. M. Choa-Duterre for histological sections.


  1. Ara T, Nakamura Y, Egawa T, Sugiyama T, Abe K, Kishimoto T, Matsui Y, Nagasawa T (2003) Impaired colonization of the gonads by primordial gem cells in mice lacking a chemokine, stromal cell-derived factor-1 (SDF-1). Proc Natl Acad Sci 100:5319–5323CrossRefPubMedPubMedCentralGoogle Scholar
  2. Bendel-Stenze MR, Gomperts M, Anderson R, Heasman J, Wylie C (2000) The role of cadherins during primordial germ cell migration and early gonad formation in the mouse. Mech Dev 91:143–152CrossRefGoogle Scholar
  3. Buchner J (1999) HSP90 & Co.-a holding for folding. Trends Biochem Sci 24:136–141Google Scholar
  4. Castrillon DH, Quade BJ, Wang TY, Quigley C, Crum CP (2000) The human VASA gene is specifically expressed in the germ cell lineage. Proc Natl Acad Sci U S A 97:9585–9590CrossRefPubMedPubMedCentralGoogle Scholar
  5. Chen WS, Chen CC, Chen LL, Lee CC, Huang TS (2013) Secreted heat shock protein 90α (HSP90α) induces nuclear factor-κB-mediated TCF12 protein expression to down-regulate E-cadherin and to enhance colorectal cancer cell migration and invasion. J Biol Chem 288:9001–9010CrossRefPubMedPubMedCentralGoogle Scholar
  6. Chiquoine DA (1954) The identification, origin, and migration of the primordial germ cells in the mouse embryo. Anat Rec 118:135–146CrossRefPubMedPubMedCentralGoogle Scholar
  7. D’Costa S, Petitte JN (1999) Characterization of stage-specific embryonic antigen-1 (SSEA-1) expression during early development of the turkey embryo. Int J Dev Biol 43:349–356PubMedPubMedCentralGoogle Scholar
  8. De Felici M (2013) Origin, migration, and proliferation of human primordial germ cells. In: Coticchio B, De Santis L (eds) Oogenesis. Springer, London, pp 19–37CrossRefGoogle Scholar
  9. Deborah LR, Bennett LK (1993) glh-1, a germ-line putative RNA helicase from Caenorhabditis, has four zinc fingers. Proc Natl Acad Sci U S A 90:9300–9304CrossRefGoogle Scholar
  10. Doitsidou M, Reichman-Fried M, Stebler J, Koprunner M, Dorries J, Meyer D, Esguerra CV, Leung T, Raz E (2002) Guidance of primordial germ cell migration by the chemokine SDF-1. Cell 111:647–659CrossRefPubMedPubMedCentralGoogle Scholar
  11. Dudley BM, Runyan C, Takeuchi Y, Schaible K, Molyneaux K (2007) BMP signaling regulates PGC numbers and motility in organ culture. Mech Dev 124:68–77CrossRefPubMedPubMedCentralGoogle Scholar
  12. Dustin AP (1910) L’origine et l’évolution des gonocytes chez les reptiles. Arch Biol 25:495–534Google Scholar
  13. Everett NB (1945) The present status of the germ cell problem in vertebrates. Biol Rev Camb Philos Soc 20:45–55CrossRefGoogle Scholar
  14. Felix W (1911) Die Entwicklung der Harm- und Geschlechtsorgane. In: Keibel-Mall Handbuch der Entwicklungageschichte des Menschen, vol 2. Hirzel, Leipzig, pp 732–955Google Scholar
  15. Fox N, Damjanov I, Martinez-Hernandez A, Knowel BB, Solter D (1981) Immunohistochemical localization of the early embryonic antigen (SSEA-1) in postimplantation mouse embryos and fetal and adult tissue. Dev Biol 83:391–398CrossRefPubMedPubMedCentralGoogle Scholar
  16. Fujiwara Y, Komiya T, Kawabata H, Sato M, Fujimoto H, Furusawa M, Noce T (1994) Isolation of a DEAD-family protein gene that encodes a murine homolog of Drosophila vasa and its specific expression in germ cell lineage. Proc Natl Acad Sci U S A 91:12258–12262CrossRefPubMedPubMedCentralGoogle Scholar
  17. Fuss A (1911) Uber extraregionare Geschlechtszellen bei einem menschlichen Embryo von 4 Wochen. Anat Am 39:407–409Google Scholar
  18. Gamo H (1961) On the origin of germ cells and formation of gonad primordia in the medaka, Olyzias latipes. J Zool 13:101–115Google Scholar
  19. Ginsburg M (1997) Primordial germ cell development in avians. Poult Sci 76:91–95CrossRefPubMedPubMedCentralGoogle Scholar
  20. Ginsburg M, Snow MHL, Mc Laren A (1990) Primordial germ cells in the mouse embryo during gastrulation. Development 110:521–528PubMedPubMedCentralGoogle Scholar
  21. Gu Y, Runyan C, Shoemaker A, Surani A, Wylie C (2006) Steel factor controls primordial germ cell survival and motility from the time of their specification in the allantois, and provides a continuous niche throughout their migration. Development 136:1295–1303CrossRefGoogle Scholar
  22. Hahnel AC, Eddy EM (1986) Cell surface markers of mouse primordial germ cells defined by two monoclonal antibodies. Gamete Res 15:1235–1244CrossRefGoogle Scholar
  23. Hargitt GT (1925) The formation of the sex glands and germ cells of mammals. J Morph Physiol 40:517–557CrossRefGoogle Scholar
  24. Haupt A, Joberty G, Bantscheff M, Frohlich H, Stehr H, Schweiger MR, Fischer A, Kerick M, Boerno ST, Dahl A, Lappe M, Lehrach H, Gonzalez C, Drewes G, Lange BMH (2012) Hsp90 inhibition differentially destabilizes MAP linase and TGF-beta signaling components in cancer cells revealed by kinase-targeted chemoproteomics. BMC Cancer 12:38–50CrossRefPubMedPubMedCentralGoogle Scholar
  25. Heys F (1931) The problem of the origin of germ cells. Q Rev Biol 6:1–45CrossRefGoogle Scholar
  26. Kazama-Wakabayashi M, Yamaha E, Yamazaki F (1999) The elimination and duplication of lower part of blastoderm effects on the number of primordial germ cells in goldfish. Fish Sci 65:577–582CrossRefGoogle Scholar
  27. Koyasu S, Nishida E, Kodawaki T, Matsuzaki F, Lida K, Harada F, Kasuga M, Sakai H, YaharaTwo I (1986) Mammalian heat shock proteins, HSP90 and HSP100, are actin-binding proteins. Proc Natl Acad Sci U S A 83:8054–8058CrossRefPubMedPubMedCentralGoogle Scholar
  28. Lasko PF, Ashburner M (1988) The product of the Drosophila gene vasa is very similar to eukaryotic initiation factor-4A. Nature 335:611–617CrossRefPubMedPubMedCentralGoogle Scholar
  29. Lawson KA, Ray Dunn N, Roelen BAJ, Zeinstra LM, Davis AM, Wright CVE, Korving JPWFM, Hogan BLM (1999) Bmp4 is required for the generation of primordial germ cells in the mouse embryo. Genes Dev 13:424–436CrossRefPubMedPubMedCentralGoogle Scholar
  30. Lejong M, Choa-Duterre M, Vanmuylder N, Louryan S (2018) Geldanamycin administration reduces the amount of primordial germ cells in the mouse embryo. Morphologie 102: 219-224.
  31. Lin TY, Bear M, Du Z, Foley KP, Ying W, Barsoum J, London C (2008) The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors. Exp Hematol 36:1266–1277CrossRefPubMedPubMedCentralGoogle Scholar
  32. Louryan S, Evrard L, Glineur R, Vanmuylder N (2002) Protéines de choc thermique, embryogenèse et évolution. Bull Mem Acad R Med Belg 157:293–299PubMedGoogle Scholar
  33. Louryan S, Vanmuylder N, Lambot MA, Rooze M (2003) HSP86: un rôle dans l’évolution humaine ? Anthropol Praehist 114:1–5Google Scholar
  34. Machev N, Fuhrmann G, Viville S (2004) Ontogénèse des cellules germinales primordiales. Med Sci 20:1091–1095Google Scholar
  35. McKay D, Hertig AT, Adams EC, Danziger S (1953) Histochemical observations on the germ cells of human embryos. Anat Rec 17:201–219CrossRefGoogle Scholar
  36. McLaren A (2003) Primordial germ cells in the mouse. Dev Biol 262:1–15CrossRefGoogle Scholar
  37. Miyata A, Yahara I (1992) The 90-kDa heat shock protein, HSP90, binds and protects casein kinase II from self-aggregation and enhances its kinase activity. J Biol Chem 7:7042–7047Google Scholar
  38. Molyneaux K, Wylie C (2004) Primordial germ cell migration. Int J Dev Biol 48:537–544CrossRefGoogle Scholar
  39. Nagai T, Yamaha E, Arai K (2001) Histological differentiation of primordial germ cells in zebrafish. Zool Sci 18:215–223CrossRefGoogle Scholar
  40. Neckers L, Workman P (2012) Hsp90 molecular chaperone inhibitors: are we there yet? Clin Cancer Res 18:64–76CrossRefPubMedPubMedCentralGoogle Scholar
  41. Niewkoop D, Sutasurya LA (1979) Primordial germ cells in the chordates. Cambridge University Press, CambridgeGoogle Scholar
  42. Noce T, Okamoto-Ito S, Tsunekawa N (2001) Vasa homolog genes in mammalian germ cell development. Cell Struct Funct 26:131–136CrossRefPubMedPubMedCentralGoogle Scholar
  43. Olsen LC, Aasland R, Fjose A (1997) A vasa-like gene in zebrafish identifies putative primordial germ cells. Mech Dev 66:95–105CrossRefPubMedPubMedCentralGoogle Scholar
  44. Peuβ R, Eggert H, Armitage SAO, Kurtz J (2015) Downregulation of the evolutionary capacitor Hsp90 is mediated by social cues. Proc R Soc B 282:20152041. Scholar
  45. Pfeiffer J, Tarbashevich K, Bandemer J, Palm T, Raz E (2018) Rapid progression through the cell cycle ensures efficient migration of primordial germ cells-the role of Hsp90. Dev Biol 436:84–93CrossRefPubMedPubMedCentralGoogle Scholar
  46. Queitsch C, Sangster TA, Lindquist S (2002) Hsp9O as a capacitor of phenotypic variation. Nature 417:618–624CrossRefGoogle Scholar
  47. Rohner N, Jarosz DF, Kowalko JE, Yoshizawa M, Jeffery WR, Borowsky RL, Lindquist S, Tabin CJ (2013) Cryptic variations on morphological evolution: HSP90 as a capacitor for loss of eyes in cavefish. Science 342:1372–1375CrossRefPubMedPubMedCentralGoogle Scholar
  48. Rutherford SL, Lindquist S (1998) Hsp90 as a capacitor for morphological evolution. Nature 396:336–342CrossRefGoogle Scholar
  49. Ryan CP, Brownlie JC, Whyard S (2016) Hsp90 and physiological stress are linked to antonomous transposon mobility and heritable genetic change in nematodes. Genome Biol Evol 8:3794–3805PubMedPubMedCentralGoogle Scholar
  50. Saitou M, Yamaji M (2012) Primordial germ cells in mice. Cold Spring Harb Perspect Biol 4:1–19CrossRefGoogle Scholar
  51. Shevinsky LH, Knowles BB, Damjanov I, Solter D (1982) Monoclonal antibody to murine embryos defines a stage-specific embryonic antigen expressed on mouse embryos and human teratocarcinoma cells. Cell 30:697–705CrossRefPubMedPubMedCentralGoogle Scholar
  52. Simkins CS (1923) Origin and migration of the so-called primordial germ cells in the mouse and rats. Acta Zool 4:241–278CrossRefGoogle Scholar
  53. Simkins CS (1928) Origin of sex cells in man. Am J Anat 41:249–272CrossRefGoogle Scholar
  54. Sollars V, Lu X, Wang S, Garfinkel MD, Ruden DM (2003) Evidence for an epigenetic mechanism by which Hsp90 acts as a capacitor for morphological evolution. Nat Genet 33:70–74CrossRefPubMedPubMedCentralGoogle Scholar
  55. de Sousa Lopes SM, Roelen BA, Monteiro RM, Emmens R, Lin HY, Li E, Lawson KA, Mummery CL (2004) BMP signaling mediated by ALK2 in the visceral endoderm is necessary for the generation of primordial germ cells in the mouse embryo. Genes Dev 18:1838–1849CrossRefPubMedPubMedCentralGoogle Scholar
  56. Stankiewicz M, Mayer MP (2012) The universe of Hsp90. Biol Mol Concepts 3:79–97Google Scholar
  57. Stebler J, Spieler D, Slanchev K, Molyneaux K, Richter U, Cojocaru V, Tarabykin V, Wylie C, Kessel M, Raz E (2004) Primordial germ cell migration in the chick and mouse embryo: the role of the chemokine SDF-1/CXCL12. Dev Biol 272:351–361CrossRefPubMedPubMedCentralGoogle Scholar
  58. Swift CH (1914) Origin and early history of the primordial germ-cells in the chick. Am J Anat 15:483–516CrossRefGoogle Scholar
  59. Taiyab A, Rao CM (2011) Hsp90 modulates actin dynamics: inhibition of Hsp90 leads to decreased cell motility and impairs invasion. Biochim Biophys Acta 1813:213–221CrossRefPubMedPubMedCentralGoogle Scholar
  60. Takeuchi T, Tanigawa Y, Minamide R, Ikenishi K, Komiya T (2010) Analysis of SDF-1/CXCR4 signaling in primordial germ cell migration and survival or differentiation in Xenopus laevis. Mech Dev 27:146–158CrossRefGoogle Scholar
  61. Tam PP, Zhou SX (1996) The allocation of epiblast cells to ectodermal and germ-line lineages is influenced by the position of the cells in the gastrulating mouse embryo. Dev Biol 178:124–132CrossRefPubMedGoogle Scholar
  62. Terayama K, Kataoka K, Morichika K, Orii H, Watanabe K, Mochii M (2013) Developmental regulation of locomotive activity in Xenopus primordial germ cells. Develop Growth Differ 55:217–228CrossRefGoogle Scholar
  63. Timmermans LPM (1996) Origin and differentiation of primordial germ cells in vertebrates, especially fishes. Neth J Zool 46:147–162CrossRefGoogle Scholar
  64. Tsunekawa N, Naito M, Sakai Y, Nishida T, Noce T (2000) Isolation of chicken vasa homolog gene and tracing the origin of primordial germ cells. Development 127:2741–2750PubMedPubMedCentralGoogle Scholar
  65. Urven LE, Erickson CA, Abbott UK, McCarrey JR (1988) Analysis of germ line development in the chick embryo using an anti-mouse EC cell antibody. Development 103:299–304PubMedPubMedCentralGoogle Scholar
  66. Vanmuylder N, Evrard L, Daelemans P, Dourov N (2000) Chaperones in the parotid gland: localization of heat shock proteins in human salivary glands. Cells Tissues Organs 167:199–205Google Scholar
  67. Vanmuylder N, Werry-Huet A, Rooze M, Louryan S (2002) Heat shock protein HSP86 expression during mouse embryo development, especially in the germ-line. Anat Embryol 205:301–306CrossRefPubMedPubMedCentralGoogle Scholar
  68. Vanmuylder N, Lambot M-A, Rooze M, Noël J-C, Louryan S (2004) HSP86, cellules germinales at yolk sac tumor. Ann Pathol 24:473–475CrossRefPubMedPubMedCentralGoogle Scholar
  69. Vanmuylder N, Larbi H, Choa-Duterre M, Salvia P, Rooze M, Louryan S (2009) Geldanamycin administration reduces the number of HSP86-positive germ cells in the mouse embryo: preliminary results. Rev Med Brux 30:23–27PubMedPubMedCentralGoogle Scholar
  70. Wagner GP, Chiu CH, Hansen TF (1999) Is Hsp90 a regulator of evolvability? J Exp Zool 285:116–118Google Scholar
  71. Wan YQ, Zhang XM, Wang XD, Wang BJ, Wang W (2010) 17-AAG, a Hsp90 inhibitor attenuates the hypoxia induced expression of SDF-1α and ILK in mouse RPE cells. Mol Biol Rep 37:1203–1209CrossRefGoogle Scholar
  72. Wang G, Gu X, Chen L, Wang Y, Cao B, E Q (2013) Comparison of the expression of 5 heat shock proteins in benign and malignant salivary gland tumor tissues. Oncol Lett 5:1363–1369CrossRefPubMedPubMedCentralGoogle Scholar
  73. Wu J, Liu T, Rios Z, Mei Q, Lin X, Cao S (2017) Heat shock proteins and cancer. Trends Pharmacol Sci 38:226–256CrossRefPubMedPubMedCentralGoogle Scholar
  74. Yahara I (1999) The role of HSP90 in evolution. Gene Cells 4:375–379Google Scholar
  75. Ying Y, Zhao GQ (2001) Cooperation of endoderm-derived BMP2 and extraembryonic ectoderm-derived BMP4 in primordial germ cell generation in the mouse. Dev Biol 232:484–492CrossRefGoogle Scholar
  76. Ying Y, Liu XM, Marble A, Lawson KA, Zhao GQ (2000) Requirement of Bmp8b for the generation of primordial germ cells in the mouse. Mol Endocrinol 14:1053–1063CrossRefGoogle Scholar
  77. Yon N, Akbulut C (2015) Identification of primordial germ cells: cytological, histological and immunohistochemical aspects. Braz Arch Biol Technol 58:222–228CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Marie Lejong
    • 1
  • Nathalie Vanmuylder
    • 1
  • Stéphane Louryan
    • 1
    Email author
  1. 1.Laboratory of Anatomy, Biomechanics and Organogenesis, Faculty of MedicineUniversité Libre de BruxellesBrusselsBelgium

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