Skip to main content
PMC home page
The EMBO Journal logoLink to The EMBO Journal
. 1997 Dec 1;16(23):7118–7129. doi: 10.1093/emboj/16.23.7118

Defective B cell receptor-mediated responses in mice lacking the Ets protein, Spi-B.

G H Su 1, H M Chen 1, N Muthusamy 1, L A Garrett-Sinha 1, D Baunoch 1, D G Tenen 1, M C Simon 1
PMCID: PMC1170313  PMID: 9384589

Abstract

Spi-B is a hematopoietic-specific Ets family transcription factor closely related to PU.1. Previous gene targeting experiments have shown that PU.1 is essential for the production of both lymphocytes and monocytes. We have now generated mice with a null mutation at the Spi-B locus. Unlike PU.1 mutant mice, Spi-B-/- mice are viable, fertile and possess mature B and T lymphocytes. However, Spi-B-/- mice exhibit severe abnormalities in B cell function and selective T cell-dependent humoral immune responses. First, although Spi-B-/- splenic B cells respond normally to lipopolysaccharide stimulation in vitro, these B cells proliferate poorly and die in response to B cell receptor (surface IgM) cross-linking. Secondly, Spi-B-/- mice display abnormal T-dependent antigenic responses in vivo and produce low levels of antigen-specific IgG1, IgG2a and IgG2b after immunization. Finally, Spi-B-/- mice show a dramatic defect in germinal center formation and maintenance. In contrast to wild-type animals, germinal centers in Spi-B-/- mice are smaller and short-lived with significantly increased numbers of apoptotic B cells. Taken together, these results demonstrate that Spi-B is essential for antigen-dependent expansion of B cells, T-dependent immune responses and maturation of normal germinal centers in vivo.

Full Text

The Full Text of this article is available as a PDF (1.1 MB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahearn J. M., Fischer M. B., Croix D., Goerg S., Ma M., Xia J., Zhou X., Howard R. G., Rothstein T. L., Carroll M. C. Disruption of the Cr2 locus results in a reduction in B-1a cells and in an impaired B cell response to T-dependent antigen. Immunity. 1996 Mar;4(3):251–262. doi: 10.1016/s1074-7613(00)80433-1. [DOI] [PubMed] [Google Scholar]
  2. Braun T., Rudnicki M. A., Arnold H. H., Jaenisch R. Targeted inactivation of the muscle regulatory gene Myf-5 results in abnormal rib development and perinatal death. Cell. 1992 Oct 30;71(3):369–382. doi: 10.1016/0092-8674(92)90507-9. [DOI] [PubMed] [Google Scholar]
  3. Carter R. H., Fearon D. T. CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science. 1992 Apr 3;256(5053):105–107. doi: 10.1126/science.1373518. [DOI] [PubMed] [Google Scholar]
  4. Castigli E., Alt F. W., Davidson L., Bottaro A., Mizoguchi E., Bhan A. K., Geha R. S. CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation. Proc Natl Acad Sci U S A. 1994 Dec 6;91(25):12135–12139. doi: 10.1073/pnas.91.25.12135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen H. M., Zhang P., Voso M. T., Hohaus S., Gonzalez D. A., Glass C. K., Zhang D. E., Tenen D. G. Neutrophils and monocytes express high levels of PU.1 (Spi-1) but not Spi-B. Blood. 1995 May 15;85(10):2918–2928. [PubMed] [Google Scholar]
  6. Cooke M. P., Heath A. W., Shokat K. M., Zeng Y., Finkelman F. D., Linsley P. S., Howard M., Goodnow C. C. Immunoglobulin signal transduction guides the specificity of B cell-T cell interactions and is blocked in tolerant self-reactive B cells. J Exp Med. 1994 Feb 1;179(2):425–438. doi: 10.1084/jem.179.2.425. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Corcoran L. M., Karvelas M. Oct-2 is required early in T cell-independent B cell activation for G1 progression and for proliferation. Immunity. 1994 Nov;1(8):635–645. doi: 10.1016/1074-7613(94)90035-3. [DOI] [PubMed] [Google Scholar]
  8. Crissman H. A., Steinkamp J. A. Rapid, simultaneous measurement of DNA, protein, and cell volume in single cells from large mammalian cell populations. J Cell Biol. 1973 Dec;59(3):766–771. doi: 10.1083/jcb.59.3.766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Dent A. L., Shaffer A. L., Yu X., Allman D., Staudt L. M. Control of inflammation, cytokine expression, and germinal center formation by BCL-6. Science. 1997 Apr 25;276(5312):589–592. doi: 10.1126/science.276.5312.589. [DOI] [PubMed] [Google Scholar]
  10. Eisenbeis C. F., Singh H., Storb U. PU.1 is a component of a multiprotein complex which binds an essential site in the murine immunoglobulin lambda 2-4 enhancer. Mol Cell Biol. 1993 Oct;13(10):6452–6461. doi: 10.1128/mcb.13.10.6452. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Feinman R., Qiu W. Q., Pearse R. N., Nikolajczyk B. S., Sen R., Sheffery M., Ravetch J. V. PU.1 and an HLH family member contribute to the myeloid-specific transcription of the Fc gamma RIIIA promoter. EMBO J. 1994 Aug 15;13(16):3852–3860. doi: 10.1002/j.1460-2075.1994.tb06696.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Feldhaus A. L., Mbangkollo D., Arvin K. L., Klug C. A., Singh H. BLyF, a novel cell-type- and stage-specific regulator of the B-lymphocyte gene mb-1. Mol Cell Biol. 1992 Mar;12(3):1126–1133. doi: 10.1128/mcb.12.3.1126. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Fischer K. D., Zmuldzinas A., Gardner S., Barbacid M., Bernstein A., Guidos C. Defective T-cell receptor signalling and positive selection of Vav-deficient CD4+ CD8+ thymocytes. Nature. 1995 Mar 30;374(6521):474–477. doi: 10.1038/374474a0. [DOI] [PubMed] [Google Scholar]
  14. Galson D. L., Hensold J. O., Bishop T. R., Schalling M., D'Andrea A. D., Jones C., Auron P. E., Housman D. E. Mouse beta-globin DNA-binding protein B1 is identical to a proto-oncogene, the transcription factor Spi-1/PU.1, and is restricted in expression to hematopoietic cells and the testis. Mol Cell Biol. 1993 May;13(5):2929–2941. doi: 10.1128/mcb.13.5.2929. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Gavrieli Y., Sherman Y., Ben-Sasson S. A. Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992 Nov;119(3):493–501. doi: 10.1083/jcb.119.3.493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Grillot D. A., Merino R., Pena J. C., Fanslow W. C., Finkelman F. D., Thompson C. B., Nunez G. bcl-x exhibits regulated expression during B cell development and activation and modulates lymphocyte survival in transgenic mice. J Exp Med. 1996 Feb 1;183(2):381–391. doi: 10.1084/jem.183.2.381. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Hagman J., Grosschedl R. An inhibitory carboxyl-terminal domain in Ets-1 and Ets-2 mediates differential binding of ETS family factors to promoter sequences of the mb-1 gene. Proc Natl Acad Sci U S A. 1992 Oct 1;89(19):8889–8893. doi: 10.1073/pnas.89.19.8889. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hanks M., Wurst W., Anson-Cartwright L., Auerbach A. B., Joyner A. L. Rescue of the En-1 mutant phenotype by replacement of En-1 with En-2. Science. 1995 Aug 4;269(5224):679–682. doi: 10.1126/science.7624797. [DOI] [PubMed] [Google Scholar]
  19. Heydemann A., Juang G., Hennessy K., Parmacek M. S., Simon M. C. The myeloid-cell-specific c-fes promoter is regulated by Sp1, PU.1, and a novel transcription factor. Mol Cell Biol. 1996 Apr;16(4):1676–1686. doi: 10.1128/mcb.16.4.1676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Hibbs M. L., Tarlinton D. M., Armes J., Grail D., Hodgson G., Maglitto R., Stacker S. A., Dunn A. R. Multiple defects in the immune system of Lyn-deficient mice, culminating in autoimmune disease. Cell. 1995 Oct 20;83(2):301–311. doi: 10.1016/0092-8674(95)90171-x. [DOI] [PubMed] [Google Scholar]
  21. Hromas R., Orazi A., Neiman R. S., Maki R., Van Beveran C., Moore J., Klemsz M. Hematopoietic lineage- and stage-restricted expression of the ETS oncogene family member PU.1. Blood. 1993 Nov 15;82(10):2998–3004. [PubMed] [Google Scholar]
  22. Keller G., Kennedy M., Papayannopoulou T., Wiles M. V. Hematopoietic commitment during embryonic stem cell differentiation in culture. Mol Cell Biol. 1993 Jan;13(1):473–486. doi: 10.1128/mcb.13.1.473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kim U., Qin X. F., Gong S., Stevens S., Luo Y., Nussenzweig M., Roeder R. G. The B-cell-specific transcription coactivator OCA-B/OBF-1/Bob-1 is essential for normal production of immunoglobulin isotypes. Nature. 1996 Oct 10;383(6600):542–547. doi: 10.1038/383542a0. [DOI] [PubMed] [Google Scholar]
  24. Klemsz M. J., McKercher S. R., Celada A., Van Beveren C., Maki R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell. 1990 Apr 6;61(1):113–124. doi: 10.1016/0092-8674(90)90219-5. [DOI] [PubMed] [Google Scholar]
  25. Köntgen F., Grumont R. J., Strasser A., Metcalf D., Li R., Tarlinton D., Gerondakis S. Mice lacking the c-rel proto-oncogene exhibit defects in lymphocyte proliferation, humoral immunity, and interleukin-2 expression. Genes Dev. 1995 Aug 15;9(16):1965–1977. doi: 10.1101/gad.9.16.1965. [DOI] [PubMed] [Google Scholar]
  26. Laux G., Adam B., Strobl L. J., Moreau-Gachelin F. The Spi-1/PU.1 and Spi-B ets family transcription factors and the recombination signal binding protein RBP-J kappa interact with an Epstein-Barr virus nuclear antigen 2 responsive cis-element. EMBO J. 1994 Dec 1;13(23):5624–5632. doi: 10.1002/j.1460-2075.1994.tb06900.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Lin Y. H., Shin E. J., Campbell M. J., Niederhuber J. E. Transcription of the blk gene in human B lymphocytes is controlled by two promoters. J Biol Chem. 1995 Oct 27;270(43):25968–25975. doi: 10.1074/jbc.270.43.25968. [DOI] [PubMed] [Google Scholar]
  28. Matsumoto M., Lo S. F., Carruthers C. J., Min J., Mariathasan S., Huang G., Plas D. R., Martin S. M., Geha R. S., Nahm M. H. Affinity maturation without germinal centres in lymphotoxin-alpha-deficient mice. Nature. 1996 Aug 1;382(6590):462–466. doi: 10.1038/382462a0. [DOI] [PubMed] [Google Scholar]
  29. McKercher S. R., Torbett B. E., Anderson K. L., Henkel G. W., Vestal D. J., Baribault H., Klemsz M., Feeney A. J., Wu G. E., Paige C. J. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 1996 Oct 15;15(20):5647–5658. [PMC free article] [PubMed] [Google Scholar]
  30. Moreau-Gachelin F., Ray D., Mattei M. G., Tambourin P., Tavitian A. The putative oncogene Spi-1: murine chromosomal localization and transcriptional activation in murine acute erythroleukemias. Oncogene. 1989 Dec;4(12):1449–1456. [PubMed] [Google Scholar]
  31. Moreau-Gachelin F. Spi-1/PU.1: an oncogene of the Ets family. Biochim Biophys Acta. 1994 Dec 30;1198(2-3):149–163. doi: 10.1016/0304-419x(94)90011-6. [DOI] [PubMed] [Google Scholar]
  32. Mortensen R. M., Conner D. A., Chao S., Geisterfer-Lowrance A. A., Seidman J. G. Production of homozygous mutant ES cells with a single targeting construct. Mol Cell Biol. 1992 May;12(5):2391–2395. doi: 10.1128/mcb.12.5.2391. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Motoyama N., Wang F., Roth K. A., Sawa H., Nakayama K., Nakayama K., Negishi I., Senju S., Zhang Q., Fujii S. Massive cell death of immature hematopoietic cells and neurons in Bcl-x-deficient mice. Science. 1995 Mar 10;267(5203):1506–1510. doi: 10.1126/science.7878471. [DOI] [PubMed] [Google Scholar]
  34. Moulton K. S., Semple K., Wu H., Glass C. K. Cell-specific expression of the macrophage scavenger receptor gene is dependent on PU.1 and a composite AP-1/ets motif. Mol Cell Biol. 1994 Jul;14(7):4408–4418. doi: 10.1128/mcb.14.7.4408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Muthusamy N., Barton K., Leiden J. M. Defective activation and survival of T cells lacking the Ets-1 transcription factor. Nature. 1995 Oct 19;377(6550):639–642. doi: 10.1038/377639a0. [DOI] [PubMed] [Google Scholar]
  36. Nelsen B., Tian G., Erman B., Gregoire J., Maki R., Graves B., Sen R. Regulation of lymphoid-specific immunoglobulin mu heavy chain gene enhancer by ETS-domain proteins. Science. 1993 Jul 2;261(5117):82–86. doi: 10.1126/science.8316859. [DOI] [PubMed] [Google Scholar]
  37. Olson M. C., Scott E. W., Hack A. A., Su G. H., Tenen D. G., Singh H., Simon M. C. PU. 1 is not essential for early myeloid gene expression but is required for terminal myeloid differentiation. Immunity. 1995 Dec;3(6):703–714. doi: 10.1016/1074-7613(95)90060-8. [DOI] [PubMed] [Google Scholar]
  38. Oltvai Z. N., Milliman C. L., Korsmeyer S. J. Bcl-2 heterodimerizes in vivo with a conserved homolog, Bax, that accelerates programmed cell death. Cell. 1993 Aug 27;74(4):609–619. doi: 10.1016/0092-8674(93)90509-o. [DOI] [PubMed] [Google Scholar]
  39. Omori S. A., Wall R. Multiple motifs regulate the B-cell-specific promoter of the B29 gene. Proc Natl Acad Sci U S A. 1993 Dec 15;90(24):11723–11727. doi: 10.1073/pnas.90.24.11723. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Pahl H. L., Rosmarin A. G., Tenen D. G. Characterization of the myeloid-specific CD11b promoter. Blood. 1992 Feb 15;79(4):865–870. [PubMed] [Google Scholar]
  41. Pahl H. L., Scheibe R. J., Zhang D. E., Chen H. M., Galson D. L., Maki R. A., Tenen D. G. The proto-oncogene PU.1 regulates expression of the myeloid-specific CD11b promoter. J Biol Chem. 1993 Mar 5;268(7):5014–5020. [PubMed] [Google Scholar]
  42. Perez C., Coeffier E., Moreau-Gachelin F., Wietzerbin J., Benech P. D. Involvement of the transcription factor PU.1/Spi-1 in myeloid cell-restricted expression of an interferon-inducible gene encoding the human high-affinity Fc gamma receptor. Mol Cell Biol. 1994 Aug;14(8):5023–5031. doi: 10.1128/mcb.14.8.5023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Pongubala J. M., Nagulapalli S., Klemsz M. J., McKercher S. R., Maki R. A., Atchison M. L. PU.1 recruits a second nuclear factor to a site important for immunoglobulin kappa 3' enhancer activity. Mol Cell Biol. 1992 Jan;12(1):368–378. doi: 10.1128/mcb.12.1.368. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Rathmell J. C., Cooke M. P., Ho W. Y., Grein J., Townsend S. E., Davis M. M., Goodnow C. C. CD95 (Fas)-dependent elimination of self-reactive B cells upon interaction with CD4+ T cells. Nature. 1995 Jul 13;376(6536):181–184. doi: 10.1038/376181a0. [DOI] [PubMed] [Google Scholar]
  45. Rathmell J. C., Townsend S. E., Xu J. C., Flavell R. A., Goodnow C. C. Expansion or elimination of B cells in vivo: dual roles for CD40- and Fas (CD95)-ligands modulated by the B cell antigen receptor. Cell. 1996 Oct 18;87(2):319–329. doi: 10.1016/s0092-8674(00)81349-5. [DOI] [PubMed] [Google Scholar]
  46. Ray-Gallet D., Mao C., Tavitian A., Moreau-Gachelin F. DNA binding specificities of Spi-1/PU.1 and Spi-B transcription factors and identification of a Spi-1/Spi-B binding site in the c-fes/c-fps promoter. Oncogene. 1995 Jul 20;11(2):303–313. [PubMed] [Google Scholar]
  47. Ray D., Bosselut R., Ghysdael J., Mattei M. G., Tavitian A., Moreau-Gachelin F. Characterization of Spi-B, a transcription factor related to the putative oncoprotein Spi-1/PU.1. Mol Cell Biol. 1992 Oct;12(10):4297–4304. doi: 10.1128/mcb.12.10.4297. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Rosmarin A. G., Levy R., Tenen D. G. Cloning and analysis of the CD18 promoter. Blood. 1992 May 15;79(10):2598–2604. [PubMed] [Google Scholar]
  49. Rudnicki M. A., Braun T., Hinuma S., Jaenisch R. Inactivation of MyoD in mice leads to up-regulation of the myogenic HLH gene Myf-5 and results in apparently normal muscle development. Cell. 1992 Oct 30;71(3):383–390. doi: 10.1016/0092-8674(92)90508-a. [DOI] [PubMed] [Google Scholar]
  50. Rudnicki M. A., Schnegelsberg P. N., Stead R. H., Braun T., Arnold H. H., Jaenisch R. MyoD or Myf-5 is required for the formation of skeletal muscle. Cell. 1993 Dec 31;75(7):1351–1359. doi: 10.1016/0092-8674(93)90621-v. [DOI] [PubMed] [Google Scholar]
  51. Schubart D. B., Rolink A., Kosco-Vilbois M. H., Botteri F., Matthias P. B-cell-specific coactivator OBF-1/OCA-B/Bob1 required for immune response and germinal centre formation. Nature. 1996 Oct 10;383(6600):538–542. doi: 10.1038/383538a0. [DOI] [PubMed] [Google Scholar]
  52. Schuetze S., Stenberg P. E., Kabat D. The Ets-related transcription factor PU.1 immortalizes erythroblasts. Mol Cell Biol. 1993 Sep;13(9):5670–5678. doi: 10.1128/mcb.13.9.5670. [DOI] [PMC free article] [PubMed] [Google Scholar]
  53. Scott E. W., Fisher R. C., Olson M. C., Kehrli E. W., Simon M. C., Singh H. PU.1 functions in a cell-autonomous manner to control the differentiation of multipotential lymphoid-myeloid progenitors. Immunity. 1997 Apr;6(4):437–447. doi: 10.1016/s1074-7613(00)80287-3. [DOI] [PubMed] [Google Scholar]
  54. Scott E. W., Simon M. C., Anastasi J., Singh H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science. 1994 Sep 9;265(5178):1573–1577. doi: 10.1126/science.8079170. [DOI] [PubMed] [Google Scholar]
  55. Sha W. C., Liou H. C., Tuomanen E. I., Baltimore D. Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell. 1995 Jan 27;80(2):321–330. doi: 10.1016/0092-8674(95)90415-8. [DOI] [PubMed] [Google Scholar]
  56. Shin M. K., Koshland M. E. Ets-related protein PU.1 regulates expression of the immunoglobulin J-chain gene through a novel Ets-binding element. Genes Dev. 1993 Oct;7(10):2006–2015. doi: 10.1101/gad.7.10.2006. [DOI] [PubMed] [Google Scholar]
  57. Sideras P., Müller S., Shiels H., Jin H., Khan W. N., Nilsson L., Parkinson E., Thomas J. D., Brandén L., Larsson I. Genomic organization of mouse and human Bruton's agammaglobulinemia tyrosine kinase (Btk) loci. J Immunol. 1994 Dec 15;153(12):5607–5617. [PubMed] [Google Scholar]
  58. Su G. H., Ip H. S., Cobb B. S., Lu M. M., Chen H. M., Simon M. C. The Ets protein Spi-B is expressed exclusively in B cells and T cells during development. J Exp Med. 1996 Jul 1;184(1):203–214. doi: 10.1084/jem.184.1.203. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Swat W., Dessing M., von Boehmer H., Kisielow P. CD69 expression during selection and maturation of CD4+8+ thymocytes. Eur J Immunol. 1993 Mar;23(3):739–746. doi: 10.1002/eji.1830230326. [DOI] [PubMed] [Google Scholar]
  60. Tarakhovsky A., Turner M., Schaal S., Mee P. J., Duddy L. P., Rajewsky K., Tybulewicz V. L. Defective antigen receptor-mediated proliferation of B and T cells in the absence of Vav. Nature. 1995 Mar 30;374(6521):467–470. doi: 10.1038/374467a0. [DOI] [PubMed] [Google Scholar]
  61. Testi R., Phillips J. H., Lanier L. L. Leu 23 induction as an early marker of functional CD3/T cell antigen receptor triggering. Requirement for receptor cross-linking, prolonged elevation of intracellular [Ca++] and stimulation of protein kinase C. J Immunol. 1989 Mar 15;142(6):1854–1860. [PubMed] [Google Scholar]
  62. Tybulewicz V. L., Crawford C. E., Jackson P. K., Bronson R. T., Mulligan R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991 Jun 28;65(7):1153–1163. doi: 10.1016/0092-8674(91)90011-m. [DOI] [PubMed] [Google Scholar]
  63. Valentine M. A., Czernik A. J., Rachie N., Hidaka H., Fisher C. L., Cambier J. C., Bomsztyk K. Anti-immunoglobulin M activates nuclear calcium/calmodulin-dependent protein kinase II in human B lymphocytes. J Exp Med. 1995 Dec 1;182(6):1943–1949. doi: 10.1084/jem.182.6.1943. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Veis D. J., Sorenson C. M., Shutter J. R., Korsmeyer S. J. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 1993 Oct 22;75(2):229–240. doi: 10.1016/0092-8674(93)80065-m. [DOI] [PubMed] [Google Scholar]
  65. Wasylyk B., Hahn S. L., Giovane A. The Ets family of transcription factors. Eur J Biochem. 1993 Jan 15;211(1-2):7–18. doi: 10.1007/978-3-642-78757-7_2. [DOI] [PubMed] [Google Scholar]
  66. Xu J., Foy T. M., Laman J. D., Elliott E. A., Dunn J. J., Waldschmidt T. J., Elsemore J., Noelle R. J., Flavell R. A. Mice deficient for the CD40 ligand. Immunity. 1994 Aug;1(5):423–431. doi: 10.1016/1074-7613(94)90073-6. [DOI] [PubMed] [Google Scholar]
  67. Zhang D. E., Hetherington C. J., Chen H. M., Tenen D. G. The macrophage transcription factor PU.1 directs tissue-specific expression of the macrophage colony-stimulating factor receptor. Mol Cell Biol. 1994 Jan;14(1):373–381. doi: 10.1128/mcb.14.1.373. [DOI] [PMC free article] [PubMed] [Google Scholar]
  68. Zhang R., Alt F. W., Davidson L., Orkin S. H., Swat W. Defective signalling through the T- and B-cell antigen receptors in lymphoid cells lacking the vav proto-oncogene. Nature. 1995 Mar 30;374(6521):470–473. doi: 10.1038/374470a0. [DOI] [PubMed] [Google Scholar]

Articles from The EMBO Journal are provided here courtesy of Nature Publishing Group

RESOURCES