Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity

Nature volume 435, pages 354–359 (2005)Cite this article

Abstract

The serially segmented (metameric) structures of vertebrates are based on somites that are periodically formed during embryogenesis. A ‘clock and wavefront’ model has been proposed to explain the underlying mechanism of somite formation1, in which the periodicity is generated by oscillation of Notch components (the clock) in the posterior pre-somitic mesoderm (PSM)2,3,4,5,6. This temporal periodicity is then translated into the segmental units in the ‘wavefront’7,8. The wavefront is thought to exist in the anterior PSM and progress backwards at a constant rate; however, there has been no direct evidence as to whether the levels of Notch activity really oscillate and how such oscillation is translated into a segmental pattern in the anterior PSM. Here, we have visualized endogenous levels of Notch1 activity in mice, showing that it oscillates in the posterior PSM but is arrested in the anterior PSM. Somite boundaries formed at the interface between Notch1-activated and -repressed domains. Genetic and biochemical studies indicate that this interface is generated by suppression of Notch activity by mesoderm posterior 2 (Mesp2) through induction of the lunatic fringe gene (Lfng). We propose that the oscillation of Notch activity is arrested and translated in the wavefront by Mesp2.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Visualization of the Mesp2 protein and oscillation of Notch1 activity and Lfng transcripts.
Figure 2: Analyses of gene and protein expression critical for clock oscillation and its arrest.
Figure 3: Mesp2 may activate Lfng to arrest the oscillation of Notch activity in the anterior PSM.
Figure 4: Schematic representation of the regulatory mechanism underlying the clock system and of the implications of Mesp2 function in establishing the segmental boundary. 

Similar content being viewed by others

References

  1. Cooke, J. & Zeeman, E. C. A clock and wavefront model for control of the number of repeated structures during animal morphogenesis. J. Theor. Biol. 58, 455–476 (1976)

    Article  CAS  Google Scholar 

  2. Palmeirim, I., Henrique, D., Ish-Horowicz, D. & Pourquie, O. Avian hairy gene expression identifies a molecular clock linked to vertebrate segmentation and somitogenesis. Cell 91, 639–648 (1997)

    Article  CAS  Google Scholar 

  3. McGrew, M. J., Dale, J. K., Fraboulet, S. & Pourquie, O. The lunatic fringe gene is a target of the molecular clock linked to somite segmentation in avian embryos. Curr. Biol. 8, 979–982 (1998)

    Article  CAS  Google Scholar 

  4. Forsberg, H., Crozet, F. & Brown, N. A. Waves of mouse Lunatic fringe expression, in four-hour cycles at two-hour intervals, precede somite boundary formation. Curr. Biol. 8, 1027–1030 (1998)

    Article  CAS  Google Scholar 

  5. Jiang, Y. J. et al. Notch signalling and the synchronization of the somite segmentation clock. Nature 408, 475–479 (2000)

    Article  ADS  CAS  Google Scholar 

  6. Bessho, Y. et al. Dynamic expression and essential functions of Hes7 in somite segmentation. Genes Dev. 15, 2642–2647 (2001)

    Article  CAS  Google Scholar 

  7. Saga, Y. & Takeda, H. The making of the somite: molecular events in vertebrate segmentation. Nature Rev. Genet. 2, 835–845 (2001)

    Article  CAS  Google Scholar 

  8. Pourquie, O. The segmentation clock: converting embryonic time into spatial pattern. Science 301, 328–330 (2003)

    Article  ADS  CAS  Google Scholar 

  9. Saga, Y., Hata, N., Koseki, H. & Taketo, M. M. Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes Dev. 11, 1827–1839 (1997)

    Article  CAS  Google Scholar 

  10. Buchberger, A., Seidl, K., Klein, C., Eberhardt, H. & Arnold, H. H. cMeso-1, a novel bHLH transcription factor, is involved in somite formation in chicken embryos. Dev. Biol. 199, 201–215 (1998)

    Article  CAS  Google Scholar 

  11. Sparrow, D. B. et al. Thylacine 1 is expressed segmentally within the paraxial mesoderm of the Xenopus embryo and interacts with the Notch pathway. Development 125, 2041–2051 (1998)

    CAS  PubMed  Google Scholar 

  12. Sawada, A. et al. Zebrafish Mesp family genes, mesp-a and mesp-b are segmentally expressed in the presomitic mesoderm, and Mesp-b confers the anterior identity to the developing somites. Development 127, 1691–1702 (2000)

    CAS  PubMed  Google Scholar 

  13. Takahashi, Y. et al. Mesp2 initiates somite segmentation through the Notch signalling pathway. Nature Genet. 25, 390–396 (2000)

    Article  CAS  Google Scholar 

  14. Bruckner, K., Perez, L., Clausen, H. & Cohen, S. Glycosyltransferase activity of Fringe modulates Notch-Delta interactions. Nature 406, 411–415 (2000)

    Article  ADS  CAS  Google Scholar 

  15. Moloney, D. J. et al. Fringe is a glycosyltransferase that modifies Notch. Nature 406, 369–375 (2000)

    Article  ADS  CAS  Google Scholar 

  16. Dale, J. K. et al. Periodic notch inhibition by lunatic fringe underlies the chick segmentation clock. Nature 421, 275–278 (2003)

    Article  ADS  CAS  Google Scholar 

  17. Bessho, Y., Hirata, H., Masamizu, Y. & Kageyama, R. Periodic repression by the bHLH factor Hes7 is an essential mechanism for the somite segmentation clock. Genes Dev. 17, 1451–1456 (2003)

    Article  CAS  Google Scholar 

  18. Hrabe de Angelis, M., McIntyre, J. II & Gossler, A. Maintenance of somite borders in mice requires the Delta homologue DII1. Nature 386, 717–721 (1997)

    Article  ADS  CAS  Google Scholar 

  19. Evrard, Y. A., Lun, Y., Aulehla, A., Gan, L. & Johnson, R. L. lunatic fringe is an essential mediator of somite segmentation and patterning. Nature 394, 377–381 (1998)

    Article  ADS  CAS  Google Scholar 

  20. Cole, S. E., Levorse, J. M., Tilghman, S. M. & Vogt, T. F. Clock regulatory elements control cyclic expression of Lunatic fringe during somitogenesis. Dev. Cell 3, 75–84 (2002)

    Article  CAS  Google Scholar 

  21. Morales, A. V., Yasuda, Y. & Ish-Horowicz, D. Periodic Lunatic fringe expression is controlled during segmentation by a cyclic transcriptional enhancer responsive to notch signaling. Dev. Cell 3, 63–74 (2002)

    Article  CAS  Google Scholar 

  22. Bessho, Y. et al. Dynamic expression and essential functions of Hes7 in somite segmentation. Genes Dev. 15, 2642–2647 (2001)

    Article  CAS  Google Scholar 

  23. Sawada, A. et al. Fgf/MAPK signalling is a crucial positional cue in somite boundary formation. Development 128, 4873–4880 (2001)

    CAS  PubMed  Google Scholar 

  24. Dubrulle, J., McGrew, M. J. & Pourquie, O. FGF signaling controls somite boundary position and regulates segmentation clock control of spatiotemporal Hox gene activation. Cell 106, 219–232 (2001)

    Article  CAS  Google Scholar 

  25. Panin, V. M., Papayannopoulos, V., Wilson, R. & Irvine, K. D. Fringe modulates Notch–ligand interactions. Nature 387, 908–912 (1997)

    Article  ADS  CAS  Google Scholar 

  26. Haines, N. & Irvine, K. D. Glycosylation regulates Notch signalling. Nature Rev. Mol. Cell Biol. 4, 786–797 (2003)

    Article  CAS  Google Scholar 

  27. Hicks, C. et al. Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2. Nature Cell Biol. 2, 515–520 (2000)

    Article  CAS  Google Scholar 

  28. Moreno, T. A. & Kintner, C. Regulation of segmental patterning by retinoic acid signaling during Xenopus somitogenesis. Dev. Cell 6, 205–218 (2004)

    Article  CAS  Google Scholar 

  29. Sakai, Y. et al. The retinoic acid-inactivating enzyme CYP26 is essential for establishing an uneven distribution of retinoic acid along the anterio-posterior axis within the mouse embryo. Genes Dev. 15, 213–225 (2001)

    Article  CAS  Google Scholar 

  30. Nagai, T. et al. A variant of yellow fluorescent protein with fast and efficient maturation for cell-biological applications. Nature Biotechnol. 20, 87–90 (2002)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank S. Kitajima and E. Ikeno for their assistance in generating the Mesp2–venus knock-in mouse; M. Ikumi and Y. Takahashi for technical assistance and maintaining the mice used in this study; A. Gossler and R. Johnson for providing the Dll1and lunatic fringe knockout mice; and H. Hamada for CYP26a-null embryos. We also thank H. Takeda for critical reading of this manuscript. We are grateful to H. Tanaka for preparing purified Mesp2 protein. This work was supported by Grants-in-Aid for Science Research on Priority Areas (B), the Organized Research Combination System and National BioResource Project of the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Author information

Authors and Affiliations

  1. Division of Mammalian Development, National Institute of Genetics,

    Mitsuru Morimoto, Maho Endo & Yumiko Saga

  2. Sokendai, Yata 1111, 411-8540, Mishima, Japan

    Yumiko Saga

  3. Cellular & Molecular Toxicology Division, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, 158-8501, Japan

    Yu Takahashi

Authors
  1. Mitsuru Morimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yu Takahashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maho Endo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yumiko Saga
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yumiko Saga.

Ethics declarations

Competing interests

Reprints and permissions information is available at npg.nature.com/reprintsandpermissions. The authors declare no competing financial interests.

Supplementary information

Supplementary Movie 1

Changes in the expression domain of Mesp2-venus. (MOV 3804 kb)

Supplementary Figures 1-3

A knock-in strategy to generate Mesp2-venus (Fig. 1); the change of expression pattern of Mesp2-venus in vivo (Fig, 2); and double fluorescent in situ hybridization for L-fng and Mesp2 (Fig. 3). (JPG 89 kb)

Supplementary Figure 4

L-fng expression and Notch activity oscillate in the posterior PSM, but do not arrest correctly in the anterior PSM in the absence of Mesp2. (JPG 149 kb)

Supplementary Figure 5 and 6

A schematic representation of the sequential changes in the expression patterns (Fig. 5); expression pattern of Mesp2 in CYP26a-null embryos (Fig. 6). (JPG 120 kb)

Supplementary Data

This document contains legends for Supplementary Movie 1 and Supplementary Figs 1-6, and Supplementary Methods and additional references. (DOC 27 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Morimoto, M., Takahashi, Y., Endo, M. et al. The Mesp2 transcription factor establishes segmental borders by suppressing Notch activity. Nature 435, 354–359 (2005). https://doi.org/10.1038/nature03591

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature03591

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing