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:

Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor

Nature volume 391, pages 904–907 (1998)Cite this article

Abstract

To generate the full diversity of antibody heavy-chain genes, hundreds of dispersed germline V segments must undergo recombination following D–J segment joining. Here we report that this process is regulated by the α-chain of the receptor for interleukin-7, a cytokine that stimulates B-cell lymphopoiesis1. D–J joining occurs normally in immature B lymphocytes from mice lacking the α-chain of the interleukin-7 receptor (IL-7Rα). But recombination of V segments is progressively impaired as their distance increases upstream of D/J, causing infrequent rearrangement of most V segments, which markedly reduces diversity. This is not simply due to defective cell proliferation or impaired recombinase expression. Rather, germline transcripts from distal, unrearranged V segments, a marker of chromatin changes that precede recombination, are specifically silenced. So too is expression of Pax-5, which binds to heavy-chain locus control elements and normally stimulates recombination, suggesting a mechanism for these effects. Thus ligands of the interleukin-7 receptor deliver an extrinsic signal that targets V segment recombination in the heavy-chain locus by altering the accessibility of DNA substrates to the recombinase. This mechanism augments the recombinational diversity of the primary antibody repertoire.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Figure 1: Normal (D)J h recombination in IL-7Rα−/− mice.
Figure 2: Impaired targeting of recombination to 5′ V h segments.
Figure 3: Specific defect in recombination substrates rather than the recombinase machinery.
Figure 4: Expression and activity of Pax-5 are diminished in the absence of IL-7Rα.

Similar content being viewed by others

References

  1. Peschon, J. J.et al. Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice. J. Exp. Med. 180, 1955–1960 (1994).

    Article  CAS  Google Scholar 

  2. Corcoran, A. E.et al. The interleukin-7 receptor α chain transmits distinct signals for proliferation and differentiation during B lymphopoiesis. EMBO J. 15, 1924–1932 (1996).

    Article  CAS  Google Scholar 

  3. Ehlich, A., Martin, V., Muller, W. & Rajewsky, K. Analysis of the B-cell progenitor compartment at the level of single cells. Curr. Biol. 127–137 4, (1994).

    Article  Google Scholar 

  4. Chang, Y., Paige, C. J. & Wu, G. E. Enumeration and characterisation of DJh structures in mouse fetal liver. EMBO J. 11, 1891–1899 (1992).

    Article  CAS  Google Scholar 

  5. Rathbun, G. A., Capra, J. D. & Tucker, P. W. Organization of the murine immunoglobulin Vh complex in the inbred strains. EMBO J. 6, 2931–2937 (1987).

    Article  CAS  Google Scholar 

  6. Honjo, T. & Matsuda, F. in Immunoglobulin Genes2nd edn (eds Honjo, T. & Alt, F. W.) 145–172 (Academic, London, 1995).

    Book  Google Scholar 

  7. Li, Y. S., Hayakawa, K. & Hardy, R. R. The regulated expression of B lineage associated genes during B cell differentiation in bone marrow and fetal liver. J. Exp. Med. 178, 951–960 (1993).

    Article  CAS  Google Scholar 

  8. Wu, G. & Paige, C. Vh gene family utilisation in colonies derived from B and pre-B cells detected by the RNA colony blot assay. EMBO J. 5, 3475–3481 (1986).

    Article  CAS  Google Scholar 

  9. Kitamura, D. & Rajewsky, K. Targeted disruption of the µ chain membrane exon causes loss of heavy chain allelic exclusion. Nature 356, 154–156 (1992).

    Article  ADS  CAS  Google Scholar 

  10. Ehlich, A.et al. Immunoglobulin heavy and light chain genes rearrange independently at early stages of B cell development. Cell 72, 695–704 (1993).

    Article  CAS  Google Scholar 

  11. Shinkai, Y.et al. Rag-2 deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell 68, 855–867 (1992).

    Article  CAS  Google Scholar 

  12. Mombaerts, P.et al. Rag-1 deficient mice have no mature B and T lymphocytes. Cell 68, 869–877 (1992).

    Article  CAS  Google Scholar 

  13. Yancopoulos, G. & Alt, F. W. Developmentally controlled and tissue-specific expression of unrearranged Vh gene segments. Cell 40, 271–281 (1985).

    Article  CAS  Google Scholar 

  14. Alt, F. W., Blackwell, T. K. & Yancopoulos, G. D. Development of the primary antibody repertoire. Science 238, 1079–1087 (1987).

    Article  ADS  CAS  Google Scholar 

  15. Schlissel, M. S. & Baltimore, D. Activation of immunoglobulin kappa gene rearrangement correlates with induction of germline kappa gene transcription. Cell 58, 1001–1007 (1989).

    Article  CAS  Google Scholar 

  16. Yancopoulos, G. D.et al. Preferential utilisation of the most Jh-proximal Vh gene segments in pre-B cell lines. Nature 311, 727–733 (1984).

    Article  ADS  CAS  Google Scholar 

  17. Marshall, A. J., Wu, G. E. & Paige, C. J. Frequency of Vh81X usage during B cell development. J. Immunol. 2077–2084 (1996).

  18. Grawunder, U.et al. Down-regulation of RAG1 and RAG2 gene expression in preB cells after functional Ig H rearrangement. Immunity 3, 601–608 (1995).

    Article  CAS  Google Scholar 

  19. Madisen, L. & Groudine, M. Identification of a locus control region in the immunoglobulin heavy chain locus. Genes Dev. 8, 2212–2226 (1994).

    Article  CAS  Google Scholar 

  20. Michaelson, J. S., Singh, M. & Birshtein, B. K. BSAP: A player at multiple stages of B cell development. J. Immunol. 156, 2349–2351 (1996).

    CAS  PubMed  Google Scholar 

  21. Urbanek, P., Wang, Z. Q., Fetka, I., Wagner, E. F. & Busslinger, M. Complete block of early B cell differentiation and altered patterning of the posterior midbrain in mice lacking Pax5/BSAP. Cell 79, 901–912 (1994).

    Article  CAS  Google Scholar 

  22. Nutt, S. L., Urbanek, P., Rolink, A. & Busslinger, M. Essential fucntions of Pax5 (BSAP) in pro-B cell development: difference between fetal and adult B lymphopoiesis and reduced V-to-DJ recombination at the IgH locus. Genes Dev. 11, 476–491 (1997).

    Article  CAS  Google Scholar 

  23. Adams, B.et al. Pax-5 encodes the transcription factor BSAP and is expressed in B lymphocytes, the developing CNS, and adult testis. Genes Dev. 6, 1589–1607 (1992).

    Article  CAS  Google Scholar 

  24. Yancopoulos, G. D. & Alt, F. W. Regulation of the assembly and expression of variable region genes. Annu. Rev. Immunol. 4, 339–374 (1986).

    Article  CAS  Google Scholar 

  25. ten Boekel, E., Melchers, F. & Rolink, A. G. Changes in the Vh gene repertoire of developing precursor B lymphocytes in mouse bone marrow mediated by pre-B cell receptor. Immunity 7, 357–368 (1997).

    Article  CAS  Google Scholar 

  26. Hardy, R. R., Carmack, C. E., Shinton, S. A., Kemp, J. D. & Hayakawa, K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 173, 1213–1225 (1991).

    Article  CAS  Google Scholar 

  27. ten Boekel, E., Melchers, F. & Rolink, A. The status of Ig loci rearrangements in single cells from different stages of B cell development. Int. Immunol. 7, 1013–1019 (1995).

    Article  CAS  Google Scholar 

  28. Lin, H. & Grosschedl, R. Failure of B-cell differentiation in mice lacking the transcription factor EBF. Nature 376, 263–266 (1995).

    Article  ADS  CAS  Google Scholar 

  29. Schlissel, M., Voronova, M. & Baltimore, D. Helix-loop-helix transcription factor E47 activates germ-line immunoglobulin heavy-chain gene transcription in a pre-T cell line. Genes Dev. 5, 1367–1376 (1991).

    Article  CAS  Google Scholar 

  30. Kabat, E., Wu, T. T., Perry, H. M., Gottesman, K. S. & Foeller, C. Sequences of Proteins of Immunological Interest (US Department of Health and Human Services, Washington DC, 1991).

    Google Scholar 

Download references

Acknowledgements

We thank J. Peschon and J. Sims (Immunex) for the IL-7R−/− mouse strain; S. Davies and Neuberger for µMT bone marrow; C. Rada and C. Napper for DNA sequencing; and D. Fearon, M.Neuberger and K. J. Patel for critically reviewing this manuscript. A.E.C. is a Fellow of the Kay Kendall Leukaemia Research Fund. Work in A.R.V.'s laboratory is funded by the MRC.

Author information

Authors and Affiliations

  1. Medical Research Council Laboratory of Molecular Biology, CB2 2QH, Cambridge, UK

    Anne E. Corcoran, Andrew Riddell, Danielle Krooshoop & Ashok R. Venkitaraman

Authors
  1. Anne E. Corcoran
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Andrew Riddell
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Danielle Krooshoop
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ashok R. Venkitaraman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ashok R. Venkitaraman.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Corcoran, A., Riddell, A., Krooshoop, D. et al. Impaired immunoglobulin gene rearrangement in mice lacking the IL-7 receptor. Nature 391, 904–907 (1998). https://doi.org/10.1038/36122

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/36122

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