Skip to main content
SpringerLink
Log in

The Role of Hedgehog-BMP4 Signaling in the Patterning of Coelomic Mesoderm and the Onset of Gonadogenesis

  • Chapter
  • First Online:
Cell Biology of the Ovary

Abstract

All organogenesis is triggered by various cellular behaviors, based on early embryonic patterning. At the onset of the formation of the ovary or testis, a subset of coelomic epithelial cells undergo (1) epithelial-to-mesenchymal transition (EMT) and subsequent ingression, (2) gonadal differentiation, (3) maintenance of stem-like state at outer layer, and (4) acquisition of the capability to retain primordial germ cells (PGCs), in early embryos. The specific embryonic patterning responsible for these cellular behaviors represents a long-standing question in developmental biology. We addressed this question using chicken embryo, a suitable model system for cell-labeling experiments and spatiotemporally restricted gene manipulation. We found that the ventral part of medial lateral plate mesoderm (M-LPM), a precursor of coelomic epithelium, initiates gonadogenesis by undergoing ingression. By contrast, dorsal M-LPM did not undergo ingression or form gonad. Sonic Hedgehog (SHH)-BMP4 signaling establishes this dorsoventral pattern in M-LPM and initiates gonadogenesis. SHH protein is secreted from the endoderm, which is located ventral to LPM, and reaches ventral but not dorsal M-LPM. As a result, Hedgehog (Hh) signaling triggers several cellular behaviors involved in initiation of gonadogenesis in ventral M-LPM. Downstream of Hh signaling, BMP4 dynamically changes its expression and functions. It is well known that BMP4 is expressed throughout the whole LPM and establishes the mediolateral axis in the early embryo. Thereafter, at the onset of gonadogenesis, its expression is restricted to the ventral part and thus forms a dorsoventral pattern in the M-LPM in a Hh-dependent manner. As a result, BMP4 causes multiple cellular behaviors involved in gonad formation in the ventral M-LPM. Furthermore, other recent studies imply that these cellular behaviors are regulated by several molecules, such as SNAIL2, NUMB, and SDF1, at the downstream of Hh-BMP4 signaling.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
eBook
USD 16.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Li R, Albertini DF. The road to maturation: somatic cell interaction and self-organization of the mammalian oocyte. Nat Rev Mol Cell Biol. 2013;14:141–52.

    Article  CAS  Google Scholar 

  2. Young JM, McNeilly AS. Theca: the forgotten cell of the ovarian follicle. Reproduction (Cambridge, England). 2010;140:489–504.

    Article  CAS  Google Scholar 

  3. Auersperg N, Wong AS, Choi KC, Kang SK, Leung PC. Ovarian surface epithelium: biology, endocrinology, and pathology. Endocr Rev. 2001;22:255–88.

    CAS  PubMed  Google Scholar 

  4. Katabuchi H, Okamura H. Cell biology of human ovarian surface epithelial cells and ovarian carcinogenesis. Med Electr Microsc. 2003;36:74–86.

    Google Scholar 

  5. Koopman P. The curious world of gonadal development in mammals. Curr Top Dev Biol. 2016;116:537–45.

    Article  Google Scholar 

  6. Suzuki H, Kanai-Azuma M, Kanai Y. From sex determination to initial folliculogenesis in mammalian ovaries: morphogenetic waves along the anteroposterior and dorsoventral axes. Sex Dev. 2015;9:190–204.

    Article  CAS  Google Scholar 

  7. Biason-Lauber A, Chaboissier MC. Ovarian development and disease: the known and the unexpected. Semin Cell Dev Biol. 2015;45:59–67.

    Article  CAS  Google Scholar 

  8. Harikae K, Miura K, Kanai Y. Early gonadogenesis in mammals: significance of long and narrow gonadal structure. Dev Dyn. 2013;242:330–8.

    Article  CAS  Google Scholar 

  9. DeFalco T, Capel B. Gonad morphogenesis in vertebrates: divergent means to a convergent end. Annu Rev Cell Dev Biol. 2009;25:457–82.

    Article  CAS  Google Scholar 

  10. Piprek RP, Kloc M, Kubiak JZ. Early development of the gonads: origin and differentiation of the somatic cells of the genital ridges. Results Probl Cell Differ. 2016;58:1–22.

    Article  CAS  Google Scholar 

  11. Tanaka SS, Nishinakamura R. Regulation of male sex determination: genital ridge formation and Sry activation in mice. Cell Mol Life Sci. 2014;71:4781–802.

    Article  CAS  Google Scholar 

  12. Lin YT, Barske L, DeFalco T, Capel B. Numb regulates somatic cell lineage commitment during early gonadogenesis in mice. Development (Cambridge, England). 2017;144:1607–18.

    Article  CAS  Google Scholar 

  13. Richardson BE, Lehmann R. Mechanisms guiding primordial germ cell migration: strategies from different organisms. Nat Rev Mol Cell Biol. 2010;11:37–49.

    Article  CAS  Google Scholar 

  14. Yoshino T, Murai H, Saito D. Hedgehog-BMP signalling establishes dorsoventral patterning in lateral plate mesoderm to trigger gonadogenesis in chicken embryos. Nat Commun. 2016;7:12561.

    Article  CAS  Google Scholar 

  15. Atsuta Y, Takahashi Y. FGF8 coordinates tissue elongation and cell epithelialization during early kidney tubulogenesis. Development (Cambridge, England). 2015;142:2329–37.

    Article  CAS  Google Scholar 

  16. Saito D, Takase Y, Murai H, Takahashi Y. The dorsal aorta initiates a molecular cascade that instructs sympatho-adrenal specification. Science (New York, NY). 2012;336:1578–81.

    Article  CAS  Google Scholar 

  17. Pietila I, Vainio S. The embryonic aorta-gonad-mesonephros region as a generator of haematopoietic stem cells. APMIS. 2005;113:804–12.

    Article  Google Scholar 

  18. de Bruijn MF, Speck NA, Peeters MC, Dzierzak E. Definitive hematopoietic stem cells first develop within the major arterial regions of the mouse embryo. EMBO J. 2000;19:2465–74.

    Article  Google Scholar 

  19. Yoshino T, Saito D, Tadokoro R, Takahashi Y. In vivo gene manipulations of epithelial cell sheets: a novel model to study epithelial-to-mesenchymal transition. Develop Growth Differ. 2011;53:378–88.

    Article  Google Scholar 

  20. Yoshino T, et al. Interepithelial signaling with nephric duct is required for the formation of overlying coelomic epithelial cell sheet. Proc Natl Acad Sci U S Am. 2014;111:6660–5.

    Article  CAS  Google Scholar 

  21. Hen G, Friedman-Einat M, Sela-Donenfeld D. Primordial germ cells in the dorsal mesentery of the chicken embryo demonstrate left-right asymmetry and polarized distribution of the EMA1 epitope. J Anat. 2014;224:556–63.

    Article  CAS  Google Scholar 

  22. Briscoe J, Small S. Morphogen rules: design principles of gradient-mediated embryo patterning. Development (Cambridge, England). 2015;142:3996–4009.

    Article  CAS  Google Scholar 

  23. Ramsbottom SA, Pownall ME. Regulation of Hedgehog signalling inside and outside the cell. J Dev Biol. 2016;4:23.

    Article  Google Scholar 

  24. Zhang XM, Ramalho-Santos M, McMahon AP. Smoothened mutants reveal redundant roles for Shh and Ihh signaling including regulation of L/R asymmetry by the mouse node. Cell. 2001;105:781–92.

    Article  CAS  Google Scholar 

  25. Madison BB, et al. Epithelial hedgehog signals pattern the intestinal crypt-villus axis. Development (Cambridge, England). 2005;132:279–89.

    Article  CAS  Google Scholar 

  26. Auersperg N. The stem-cell profile of ovarian surface epithelium is reproduced in the oviductal fimbriae, with increased stem-cell marker density in distal parts of the fimbriae. Int J Gynecol Pathol. 2013;32:444–53.

    Article  CAS  Google Scholar 

  27. Oreal E, Mazaud S, Picard JY, Magre S, Carre-Eusebe D. Different patterns of anti-Mullerian hormone expression, as related to DMRT1, SF-1, WT1, GATA-4, Wnt-4, and Lhx9 expression, in the chick differentiating gonads. Dev Dyn. 2002;225:221–32.

    Article  CAS  Google Scholar 

  28. Kallioniemi A. Bone morphogenetic protein 4-a fascinating regulator of cancer cell behavior. Cancer Genet. 2012;205:267–77.

    Article  CAS  Google Scholar 

  29. De Robertis EM, Kuroda H. Dorsal-ventral patterning and neural induction in Xenopus embryos. Annu Rev Cell Dev Biol. 2004;20:285–308.

    Article  Google Scholar 

  30. Stern CD. Neural induction: old problem, new findings, yet more questions. Development (Cambridge, England). 2005;132:2007–21.

    Article  CAS  Google Scholar 

  31. Sukegawa A, et al. The concentric structure of the developing gut is regulated by Sonic hedgehog derived from endodermal epithelium. Development (Cambridge, England). 2000;127:1971–80.

    CAS  Google Scholar 

  32. Tonegawa A, Takahashi Y. Somitogenesis controlled by Noggin. Dev Biol. 1998;202:172–82.

    Article  CAS  Google Scholar 

  33. Tonegawa A, Funayama N, Ueno N, Takahashi Y. Mesodermal subdivision along the mediolateral axis in chicken controlled by different concentrations of BMP-4. Development (Cambridge, England). 1997;124:1975–84.

    CAS  Google Scholar 

  34. Nieto MA, Huang RY, Jackson RA, Thiery JP. EMT: 2016. Cell. 2016;166:21–45.

    Article  CAS  Google Scholar 

  35. Nakaya Y, Sheng G. An amicable separation: Chick’s way of doing EMT. Cell Adhes Migr. 2009;3:160–3.

    Article  Google Scholar 

  36. Nieto MA. Epithelial plasticity: a common theme in embryonic and cancer cells. Science (New York, NY). 2013;342:1234850.

    Article  Google Scholar 

  37. Arraf AA, Yelin R, Reshef I, Kispert A, Schultheiss TM. Establishment of the visceral embryonic midline is a dynamic process that requires bilaterally symmetric BMP signaling. Dev Cell. 2016;37:571–80.

    Article  CAS  Google Scholar 

  38. Morohashi K. The ontogenesis of the steroidogenic tissues. Genes Cells. 1997;2:95–106.

    Article  CAS  Google Scholar 

  39. Ozisik G, Achermann JC, Meeks JJ, Jameson JL. SF1 in the development of the adrenal gland and gonads. Horm Res. 2003;59:94–8.

    CAS  PubMed  Google Scholar 

  40. Birk OS, et al. The LIM homeobox gene Lhx9 is essential for mouse gonad formation. Nature. 2000;403:909–13.

    Article  CAS  Google Scholar 

  41. Hu YC, Okumura LM, Page DC. Gata4 is required for formation of the genital ridge in mice. PLoS Genet. 2013;9:e1003629.

    Article  CAS  Google Scholar 

  42. Qi X, et al. Essential role of Smad4 in maintaining cardiomyocyte proliferation during murine embryonic heart development. Dev Biol. 2007;311:136–46.

    Article  CAS  Google Scholar 

  43. Rojas A, et al. Gata4 expression in lateral mesoderm is downstream of BMP4 and is activated directly by Forkhead and GATA transcription factors through a distal enhancer element. Development (Cambridge, England). 2005;132:3405–17.

    Article  CAS  Google Scholar 

  44. Si L, et al. Smad4 mediated BMP2 signal is essential for the regulation of GATA4 and Nkx2.5 by affecting the histone H3 acetylation in H9c2 cells. Biochem Biophys Res Commun. 2014;450:81–6.

    Article  CAS  Google Scholar 

  45. Mamsen LS, Brochner CB, Byskov AG, Mollgard K. The migration and loss of human primordial germ stem cells from the hind gut epithelium towards the gonadal ridge. Int J Dev Biol. 2012;56:771–8.

    Article  CAS  Google Scholar 

  46. Stebler J, et al. Primordial germ cell migration in the chick and mouse embryo: the role of the chemokine SDF-1/CXCL12. Dev Biol. 2004;272:351–61.

    Article  CAS  Google Scholar 

  47. Dudley B, Palumbo C, Nalepka J, Molyneaux K. BMP signaling controls formation of a primordial germ cell niche within the early genital ridges. Dev Biol. 2010;343:84–93.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Stem Cell Biology and Medicine, Faculty of Medical Science, Kyushu University, Fukuoka, Japan

    Takashi Yoshino

Authors
  1. Takashi Yoshino
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takashi Yoshino .

Editor information

Editors and Affiliations

  1. Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan

    Hidetaka Katabuchi

  2. Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan

    Takashi Ohba

  3. Department of Obstetrics and Gynecology, Faculty of Life Sciences, Kumamoto University, Kumamoto, Japan

    Takeshi Motohara

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Yoshino, T. (2018). The Role of Hedgehog-BMP4 Signaling in the Patterning of Coelomic Mesoderm and the Onset of Gonadogenesis. In: Katabuchi, H., Ohba, T., Motohara, T. (eds) Cell Biology of the Ovary. Springer, Singapore. https://doi.org/10.1007/978-981-10-7941-2_2

Download citation

  • DOI: https://doi.org/10.1007/978-981-10-7941-2_2

  • Published:

  • Publisher Name: Springer, Singapore

  • Print ISBN: 978-981-10-7940-5

  • Online ISBN: 978-981-10-7941-2

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation