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.

  • Article
  • Published:

Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo

Nature Immunology volume 5, pages 638–644 (2004)Cite this article

Abstract

Notch receptors and their ligands contribute to many developmental systems, but it is not apparent how they function after birth, as their null mutants develop severe defects during embryogenesis. Here we used the Cre-loxP system to delete the Delta-like 1 gene (Dll1) after birth and demonstrated the complete disappearance of splenic marginal zone B cells in Dll1-null mice. In contrast, T cell development was unaffected. These results demonstrated that Dll1 was dispensable as a ligand for Notch1 at the branch point of T cell–B cell development but was essential for the generation of marginal zone B cells. Thus, Notch signaling is essential for lymphocyte development in vivo, but there is a redundancy of Notch-Notch ligand signaling that can drive T cell development within the thymus.

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: Dll1 expression in lymphoid tissues and generation of mice with floxed Dll1.
Figure 2: Peripheral lymphocytes seem normal in Dll1-null mice.
Figure 3: Disappearance of MZB cells from Dll1-null mice.
Figure 4: T cell development is unimpaired in Dll1-null mice.
Figure 5: Dll4 can act as a Notch ligand to direct T cell development.

Similar content being viewed by others

References

  1. Simpson, P. The Notch connection. Nature 375, 736–737 (1995).

    Article  CAS  Google Scholar 

  2. Lewis, J. Notch signaling and the control of cell fate choices in vertebrates. Semin. Cell Dev. Biol. 9, 583–589 (1998).

    Article  CAS  Google Scholar 

  3. Robey, E. Notch in vertebrates. Curr. Opin. Genet. Dev. 7, 551–557 (1997).

    Article  CAS  Google Scholar 

  4. Radtke, F., Wilson, A., Mancini, S.J.C. & MacDonald, H.R. Notch regulation of lymphocyte development and function. Nat. Immunol. 5, 247–253 (2004).

    Article  CAS  Google Scholar 

  5. Radtke, F. et al. Deficient T cell fate specification in mice with an induced inactivation of Notch1. Immunity 10, 547–558 (1999).

    Article  CAS  Google Scholar 

  6. Han, H. et al. Inducible gene knockout of transcription factor recombination signal binding protein-J reveals its essential role in T versus B lineage decision. Int. Immunol. 14, 637–645 (2002).

    Article  CAS  Google Scholar 

  7. Pui, J.C. et al. Notch1 expression in early lymphopoiesis influences B versus T lineage determination. Immunity 11, 299–308 (1999).

    Article  CAS  Google Scholar 

  8. Tanigaki, K. et al. Notch-RBP-J signaling is involved in cell fate determination of marginal zone B cells. Nat. Immunol. 3, 443–450 (2002).

    Article  CAS  Google Scholar 

  9. Saito, T. et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18, 675–685 (2003).

    Article  CAS  Google Scholar 

  10. Kuroda, K. et al. Regulation of marginal zone B cell development by MINT, a suppressor of Notch/RBP-J signaling pathway. Immunity 18, 301–312 (2003).

    Article  CAS  Google Scholar 

  11. Bettenhausen, B. Hrabe de Angelis, M., Simon, D., Guénet, J. & Gossler, A. Transient and restricted expression during mouse embryogenesis of Dll-1, a murine gene closely related to Drosophila Delta. Development 121, 2407–2418 (1995).

    CAS  PubMed  Google Scholar 

  12. Jaleco, A.C. et al. Differential effects of Notch ligands Delta-1 and Jagged-1 in human lymphoid differentiation. J. Exp. Med. 194, 991–1001 (2001).

    Article  CAS  Google Scholar 

  13. Schmitt, T.M. & Zúñiga-Pflücker, J.C. Induction of T cell development from hematopoietic progenitor cells by Delta-like-1 in vitro. Immunity 17, 749–756 (2002).

    Article  CAS  Google Scholar 

  14. Hrabe de Angelis, M., McIntyre II, J. & Gossler, A. Maintenance of somite borders in mice requires the Delta homologue Dll1. Nature 386, 717–721 (1997).

    Article  CAS  Google Scholar 

  15. Tax, F.E., Yeargers, J.J. & Thomas, J.H. Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with Delta and Serrate of Drosophila. Nature 368, 150–154 (1994).

    Article  CAS  Google Scholar 

  16. Shimizu, K. et al. Mouse Jagged1 physically interacts with Notch2 and other Notch receptors. J. Biol. Chem. 274, 32961–32969 (1999).

    Article  CAS  Google Scholar 

  17. Kühn, R., Schwenk, F., Aguet, M. & Rajewsky, K. Inducible gene targeting in mice. Science 269, 1427–1429 (1995).

    Article  Google Scholar 

  18. Martin, F. & Kearney, J.F. Marginal-zone B cells. Nat. Rev. Immunol. 2, 323–335 (2002).

    Article  CAS  Google Scholar 

  19. Roark, J.H. et al. CD1.1 expression by mouse antigen-presenting cells and marginal zone B cells. J. Immunol. 160, 3121–3127 (1998).

    CAS  Google Scholar 

  20. Won, W.J. & Kearney, J.F. CD9 is a unique marker for marginal zone B cells, B1 cells, and plasma cells in mice. J. Immunol. 168, 5605–5611 (2002).

    Article  CAS  Google Scholar 

  21. Tarutani, M. et al. Tissue-specific knockout of the mouse Pig-a gene reveals important roles for GPI-anchored proteins in skin development. Proc. Natl. Acad. Sci. USA 94, 7400–7405 (1997).

    Article  CAS  Google Scholar 

  22. Sano, S. et al. Stat3 in thymic epithelial cells is essential for postnatal maintenance of thymic architecture and thymocyte survival. Immunity 15, 261–273 (2001).

    Article  CAS  Google Scholar 

  23. Schutter, J.R. et al. Dll4, a novel Notch ligand expressed in arterial endothelium. Genes Dev. 14, 1313–1318 (2000).

    Google Scholar 

  24. Mailhos, C. et al. Delta4, an endothelial specific Notch ligand expressed at sites of physiological and tumor angiogenesis. Differentiation 69, 135–144 (2001).

    Article  CAS  Google Scholar 

  25. Kodama, H., Nose, M., Niida, S., Nishikawa, S. & Nishikawa, S. Involvement of the c-kit receptor in the adhesion of hematopoietic stem cells to stromal cells. Exp. Hematol. 22, 979–984 (1994).

    CAS  PubMed  Google Scholar 

  26. Nishikawa, S. et al. In vitro generation of lymphohematopoietic cells from endothelial cells purified from murine embryos. Immunity 8, 761–769 (1998).

    Article  CAS  Google Scholar 

  27. Schmitt, T.M. et al. Induction of T cell development and establishment of T cell competence from embryonic stem cells differentiated in vitro. Nat. Immunol. 5, 410–417 (2004).

    Article  CAS  Google Scholar 

  28. Hozumi, K., Abe, N., Chiba, S., Hirai, H. & Habu, S. Active form of Notch members can enforce T lymphopoiesis on lymphoid progenitors in the monolayer culture specific for B cell development. J. Immunol. 170, 4973–4979 (2003).

    Article  CAS  Google Scholar 

  29. Yan, X. et al. A novel Notch ligand, Dll4, induces T-cell leukemia/lymphoma when overexpressed in mice by retroviral-mediated gene transfer. Blood 13, 3793–3799 (2001).

    Article  Google Scholar 

  30. Shimizu, K. et al. Integrity of intracellular domain of Notch ligand is indispensable for cleavage required for release of the Notch2 intracellular domain. EMBO J. 21, 294–302 (2002).

    Article  CAS  Google Scholar 

  31. Dunwoodie, S.L., Henrique, D., Harrison, S.M. & Beddington, R.S.P. Mouse Dll3: a novel divergent Delta gene which may complement the function of other Delta homologues during early pattern formation in the mouse embryo. Development 124, 3065–3076 (1997).

    CAS  PubMed  Google Scholar 

  32. Felli, M.P. et al. Expression pattern of Notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development. Int. Immunol. 11, 1017–1025 (1999).

    Article  CAS  Google Scholar 

  33. Kaneta, M. et al. A role for Pref-1 and HES-1 in thymocyte development. J. Immunol. 164, 256–264 (2000).

    Article  CAS  Google Scholar 

  34. Dammers, P.M., de Boer, N.K., Deenen, G.J., Nieuwenhuis, P. & Kroese, F.G. The origin of marginal zone B cells in the rat. Eur. J. Immunol. 29, 1522–1531 (1999).

    Article  CAS  Google Scholar 

  35. Cariappa, A. et al. The follicular versus marginal zone B lymphocyte cell fate decision is regulated by Aiolos, Btk, and CD21. Immunity 14, 603–615 (2001).

    Article  CAS  Google Scholar 

  36. Rickert, R.C., Roes, J. & Rajewsky, K. B lymphocyte-specific, Cre-mediated mutagenesis in mice. Nucleic Acids. Res. 25, 1317–1318 (1997).

    Article  CAS  Google Scholar 

  37. Hozumi, K. et al. Pro-T cells in fetal thymus express c-kit and RAG2 but do not rearrange the gene encoding the T cell receptor β chain. Eur. J. Immunol. 24, 1339–1344 (1994).

    Article  CAS  Google Scholar 

  38. Hozumi, K., Kobori, A., Sato, T., Nishimura, T. & Habu, S. Transcription and demethylation of TCR β gene initiate prior to the gene rearrangement in c-kit+ thymocytes with CD3 expression: evidence of T cell commitment in the thymus. Int. Immunol. 8, 1473–1481 (1996).

    Article  CAS  Google Scholar 

  39. Aifantis, I., Buer, J., von Boehmer, H. & Azogui, O. Essential role of the pre-T cell receptor in allelic exclusion of the T cell receptor β locus. Immunity 7, 601–607 (1997).

    Article  CAS  Google Scholar 

  40. Gärtener, F. et al. Immature thymocytes employ distinct signaling pathways for allelic exclusion versus differentiation and expansion. Immunity 10, 537–546 (1999).

    Article  Google Scholar 

Download references

Acknowledgements

We thank H.-R. Rodewald (Ulm University, Ulm, Germany) for comments and critical reading of the manuscript; T. Higgins and I. Rosewell for technical assistance; J. Ito for operating the confocal laser microscope; and Y. Okada and S. Ueno for operating the cell sorter. Supported in part by Scientific Research B (S.H.), the Ministry of Education, Culture, Sports, Science and Technology of Japan, Grant-in-Aid for Young Scientists (K.H.) and Naito Memorial Foundation (K.H.).

Author information

Authors and Affiliations

  1. Department of Immunology, Tokai University School of Medicine, Bohseidai, Isehara, 259-1193, Kanagawa, Japan

    Katsuto Hozumi, Naoko Negishi, Daisuke Suzuki, Natsumi Abe & Sonoko Habu

  2. Center for Embryogenesis and Organogenesis, Tokai University School of Medicine, Bohseidai, Isehara, 259-1193, Kanagawa, Japan

    Katsuto Hozumi, Naoko Negishi & Sonoko Habu

  3. Lymphocyte Molecular Biology Laboratory, Cancer Research UK, 44 Lincoln's Inn Field, London, WC2A 3PX, UK

    Katsuto Hozumi & Michael J Owen

  4. Central Institute for Experimental Animals, Nogawa, Kawasaki, 216-0001, Kanagawa, Japan

    Yusuke Sotomaru & Norikazu Tamaoki

  5. Developmetal Genetics Laboratory, Cancer Research UK, 44 Lincoln's Inn Field, London, WC2A 3PX, UK

    Carolina Mailhos & David Ish-Horowicz

  6. GlaxoSmithKline, Gunnels Wood Road, Stevenage, SG1 2NY, Herts, UK

    Michael J Owen

Authors
  1. Katsuto Hozumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Naoko Negishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Daisuke Suzuki
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natsumi Abe
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yusuke Sotomaru
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Norikazu Tamaoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Carolina Mailhos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. David Ish-Horowicz
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Sonoko Habu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Michael J Owen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sonoko Habu.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hozumi, K., Negishi, N., Suzuki, D. et al. Delta-like 1 is necessary for the generation of marginal zone B cells but not T cells in vivo. Nat Immunol 5, 638–644 (2004). https://doi.org/10.1038/ni1075

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni1075

This article is cited by

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