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. 1997 Jun;17(6):3335–3344. doi: 10.1128/mcb.17.6.3335

The absence of the transcription activator TFE3 impairs activation of B cells in vivo.

K Merrell 1, S Wells 1, A Henderson 1, J Gorman 1, F Alt 1, A Stall 1, K Calame 1
PMCID: PMC232186  PMID: 9154832

Abstract

TFE3 is a ubiquitously expressed member of the TFE3/mi family of basic helix loop helix zipper transcription factors. TFE3 binds to muE3 sites located in the immunoglobulin heavy-chain (IgH) intronic enhancer, heavy-chain variable region promoters, the Ig kappa intronic enhancer, and regulatory sites in other genes. To understand the role of TFE3 in Ig expression and lymphoid development, we used embryonic stem (ES) cell-mediated gene targeting and RAG2-/- blastocyst complementation to generate mice which lack TFE3 in their B and T lymphocytes. TFE3- ES cells fully reconstitute the B- and T-cell compartments, giving rise to normal patterns of IgM+ B220+ B cells and CD4+ and CD8+ T cells. However, TFE3- B cells show several defects consistent with poor B-cell activation. Serum IgM levels are reduced twofold and IgG and IgA isotypes are reduced three- to sixfold in the TFE3- chimeras even though in vitro, the TFE3- splenocytes secrete normal levels of all isotypes in response to lipopolysaccharide activation. Peripheral TFE3- B cells also show reduced surface expression of CD23 and CD24 (heat-stable antigen).

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Selected References

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  1. Alterman L. A., Crispe I. N., Kinnon C. Characterization of the murine heat-stable antigen: an hematolymphoid differentiation antigen defined by the J11d, M1/69 and B2A2 antibodies. Eur J Immunol. 1990 Jul;20(7):1597–1602. doi: 10.1002/eji.1830200728. [DOI] [PubMed] [Google Scholar]
  2. Armitage R. J., Fanslow W. C., Strockbine L., Sato T. A., Clifford K. N., Macduff B. M., Anderson D. M., Gimpel S. D., Davis-Smith T., Maliszewski C. R. Molecular and biological characterization of a murine ligand for CD40. Nature. 1992 May 7;357(6373):80–82. doi: 10.1038/357080a0. [DOI] [PubMed] [Google Scholar]
  3. Artandi S. E., Cooper C., Shrivastava A., Calame K. The basic helix-loop-helix-zipper domain of TFE3 mediates enhancer-promoter interaction. Mol Cell Biol. 1994 Dec;14(12):7704–7716. doi: 10.1128/mcb.14.12.7704. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Artandi S. E., Merrell K., Avitahl N., Wong K. K., Calame K. TFE3 contains two activation domains, one acidic and the other proline-rich, that synergistically activate transcription. Nucleic Acids Res. 1995 Oct 11;23(19):3865–3871. doi: 10.1093/nar/23.19.3865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Bain G., Maandag E. C., Izon D. J., Amsen D., Kruisbeek A. M., Weintraub B. C., Krop I., Schlissel M. S., Feeney A. J., van Roon M. E2A proteins are required for proper B cell development and initiation of immunoglobulin gene rearrangements. Cell. 1994 Dec 2;79(5):885–892. doi: 10.1016/0092-8674(94)90077-9. [DOI] [PubMed] [Google Scholar]
  6. Beckmann H., Su L. K., Kadesch T. TFE3: a helix-loop-helix protein that activates transcription through the immunoglobulin enhancer muE3 motif. Genes Dev. 1990 Feb;4(2):167–179. doi: 10.1101/gad.4.2.167. [DOI] [PubMed] [Google Scholar]
  7. Blackwell T. K., Huang J., Ma A., Kretzner L., Alt F. W., Eisenman R. N., Weintraub H. Binding of myc proteins to canonical and noncanonical DNA sequences. Mol Cell Biol. 1993 Sep;13(9):5216–5224. doi: 10.1128/mcb.13.9.5216. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carr C. S., Sharp P. A. A helix-loop-helix protein related to the immunoglobulin E box-binding proteins. Mol Cell Biol. 1990 Aug;10(8):4384–4388. doi: 10.1128/mcb.10.8.4384. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Carter R. S., Ordentlich P., Kadesch T. Selective utilization of basic helix-loop-helix-leucine zipper proteins at the immunoglobulin heavy-chain enhancer. Mol Cell Biol. 1997 Jan;17(1):18–23. doi: 10.1128/mcb.17.1.18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chen J., Lansford R., Stewart V., Young F., Alt F. W. RAG-2-deficient blastocyst complementation: an assay of gene function in lymphocyte development. Proc Natl Acad Sci U S A. 1993 May 15;90(10):4528–4532. doi: 10.1073/pnas.90.10.4528. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Chen J., Stewart V., Spyrou G., Hilberg F., Wagner E. F., Alt F. W. Generation of normal T and B lymphocytes by c-jun deficient embryonic stem cells. Immunity. 1994 Apr;1(1):65–72. doi: 10.1016/1074-7613(94)90010-8. [DOI] [PubMed] [Google Scholar]
  12. Chen J., Young F., Bottaro A., Stewart V., Smith R. K., Alt F. W. Mutations of the intronic IgH enhancer and its flanking sequences differentially affect accessibility of the JH locus. EMBO J. 1993 Dec;12(12):4635–4645. doi: 10.1002/j.1460-2075.1993.tb06152.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cogné M., Lansford R., Bottaro A., Zhang J., Gorman J., Young F., Cheng H. L., Alt F. W. A class switch control region at the 3' end of the immunoglobulin heavy chain locus. Cell. 1994 Jun 3;77(5):737–747. doi: 10.1016/0092-8674(94)90057-4. [DOI] [PubMed] [Google Scholar]
  14. Czerkinsky C. C., Nilsson L. A., Nygren H., Ouchterlony O., Tarkowski A. A solid-phase enzyme-linked immunospot (ELISPOT) assay for enumeration of specific antibody-secreting cells. J Immunol Methods. 1983 Dec 16;65(1-2):109–121. doi: 10.1016/0022-1759(83)90308-3. [DOI] [PubMed] [Google Scholar]
  15. Delespesse G., Suter U., Mossalayi D., Bettler B., Sarfati M., Hofstetter H., Kilcherr E., Debre P., Dalloul A. Expression, structure, and function of the CD23 antigen. Adv Immunol. 1991;49:149–191. doi: 10.1016/s0065-2776(08)60776-2. [DOI] [PubMed] [Google Scholar]
  16. Dierks S. E., Campbell K. A., Studer E. J., Conrad D. H. Molecular mechanisms of murine Fc epsilon RII/CD23 regulation. Mol Immunol. 1994 Oct;31(15):1181–1189. doi: 10.1016/0161-5890(94)90032-9. [DOI] [PubMed] [Google Scholar]
  17. Ephrussi A., Church G. M., Tonegawa S., Gilbert W. B lineage--specific interactions of an immunoglobulin enhancer with cellular factors in vivo. Science. 1985 Jan 11;227(4683):134–140. doi: 10.1126/science.3917574. [DOI] [PubMed] [Google Scholar]
  18. Ernst P., Smale S. T. Combinatorial regulation of transcription II: The immunoglobulin mu heavy chain gene. Immunity. 1995 May;2(5):427–438. doi: 10.1016/1074-7613(95)90024-1. [DOI] [PubMed] [Google Scholar]
  19. Fisher D. E., Carr C. S., Parent L. A., Sharp P. A. TFEB has DNA-binding and oligomerization properties of a unique helix-loop-helix/leucine-zipper family. Genes Dev. 1991 Dec;5(12A):2342–2352. doi: 10.1101/gad.5.12a.2342. [DOI] [PubMed] [Google Scholar]
  20. Georgopoulos K., Bigby M., Wang J. H., Molnar A., Wu P., Winandy S., Sharpe A. The Ikaros gene is required for the development of all lymphoid lineages. Cell. 1994 Oct 7;79(1):143–156. doi: 10.1016/0092-8674(94)90407-3. [DOI] [PubMed] [Google Scholar]
  21. Gregor P. D., Sawadogo M., Roeder R. G. The adenovirus major late transcription factor USF is a member of the helix-loop-helix group of regulatory proteins and binds to DNA as a dimer. Genes Dev. 1990 Oct;4(10):1730–1740. doi: 10.1101/gad.4.10.1730. [DOI] [PubMed] [Google Scholar]
  22. Gross J. A., St John T., Allison J. P. The murine homologue of the T lymphocyte antigen CD28. Molecular cloning and cell surface expression. J Immunol. 1990 Apr 15;144(8):3201–3210. [PubMed] [Google Scholar]
  23. 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. 1991 May 1;173(5):1213–1225. doi: 10.1084/jem.173.5.1213. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Henthorn P. S., Stewart C. C., Kadesch T., Puck J. M. The gene encoding human TFE3, a transcription factor that binds the immunoglobulin heavy-chain enhancer, maps to Xp11.22. Genomics. 1991 Oct;11(2):374–378. doi: 10.1016/0888-7543(91)90145-5. [DOI] [PubMed] [Google Scholar]
  25. Hodgkinson C. A., Moore K. J., Nakayama A., Steingrímsson E., Copeland N. G., Jenkins N. A., Arnheiter H. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell. 1993 Jul 30;74(2):395–404. doi: 10.1016/0092-8674(93)90429-t. [DOI] [PubMed] [Google Scholar]
  26. Jeannotte L., Ruiz J. C., Robertson E. J. Low level of Hox1.3 gene expression does not preclude the use of promoterless vectors to generate a targeted gene disruption. off. Mol Cell Biol. 1991 Nov;11(11):5578–5585. doi: 10.1128/mcb.11.11.5578. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Kantor A. B., Stall A. M., Adams S., Herzenberg L. A., Herzenberg L. A. Differential development of progenitor activity for three B-cell lineages. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3320–3324. doi: 10.1073/pnas.89.8.3320. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kay R., Takei F., Humphries R. K. Expression cloning of a cDNA encoding M1/69-J11d heat-stable antigens. J Immunol. 1990 Sep 15;145(6):1952–1959. [PubMed] [Google Scholar]
  29. Kehry M. R., Castle B. E. Regulation of CD40 ligand expression and use of recombinant CD40 ligand for studying B cell growth and differentiation. Semin Immunol. 1994 Oct;6(5):287–294. doi: 10.1006/smim.1994.1037. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. MacLennan I. C. Germinal centers. Annu Rev Immunol. 1994;12:117–139. doi: 10.1146/annurev.iy.12.040194.001001. [DOI] [PubMed] [Google Scholar]
  32. Malynn B. A., Demengeot J., Stewart V., Charron J., Alt F. W. Generation of normal lymphocytes derived from N-myc-deficient embryonic stem cells. Int Immunol. 1995 Oct;7(10):1637–1647. doi: 10.1093/intimm/7.10.1637. [DOI] [PubMed] [Google Scholar]
  33. Melchers F., Haasner D., Grawunder U., Kalberer C., Karasuyama H., Winkler T., Rolink A. G. Roles of IgH and L chains and of surrogate H and L chains in the development of cells of the B lymphocyte lineage. Annu Rev Immunol. 1994;12:209–225. doi: 10.1146/annurev.iy.12.040194.001233. [DOI] [PubMed] [Google Scholar]
  34. Peterson C. L., Calame K. Proteins binding to site C2 (muE3) in the immunoglobulin heavy-chain enhancer exist in multiple oligomeric forms. Mol Cell Biol. 1989 Feb;9(2):776–786. doi: 10.1128/mcb.9.2.776. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Pfeffer K., Mak T. W. Lymphocyte ontogeny and activation in gene targeted mutant mice. Annu Rev Immunol. 1994;12:367–411. doi: 10.1146/annurev.iy.12.040194.002055. [DOI] [PubMed] [Google Scholar]
  36. Richards M. L., Katz D. H. Regulation of the murine Fc epsilon RII (CD23) gene. Functional characterization of an IL-4 enhancer element. J Immunol. 1994 Apr 1;152(7):3453–3466. [PubMed] [Google Scholar]
  37. Robertson E. J. Using embryonic stem cells to introduce mutations into the mouse germ line. Biol Reprod. 1991 Feb;44(2):238–245. doi: 10.1095/biolreprod44.2.238. [DOI] [PubMed] [Google Scholar]
  38. Robertson E., Bradley A., Kuehn M., Evans M. Germ-line transmission of genes introduced into cultured pluripotential cells by retroviral vector. Nature. 1986 Oct 2;323(6087):445–448. doi: 10.1038/323445a0. [DOI] [PubMed] [Google Scholar]
  39. Roman C., Cohn L., Calame K. A dominant negative form of transcription activator mTFE3 created by differential splicing. Science. 1991 Oct 4;254(5028):94–97. doi: 10.1126/science.1840705. [DOI] [PubMed] [Google Scholar]
  40. Roman C., Matera A. G., Cooper C., Artandi S., Blain S., Ward D. C., Calame K. mTFE3, an X-linked transcriptional activator containing basic helix-loop-helix and zipper domains, utilizes the zipper to stabilize both DNA binding and multimerization. Mol Cell Biol. 1992 Feb;12(2):817–827. doi: 10.1128/mcb.12.2.817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Sarfati M., Fournier S., Wu C. Y., Delespesse G. Expression, regulation and function of human Fc epsilon RII (CD23) antigen. Immunol Res. 1992;11(3-4):260–272. doi: 10.1007/BF02919132. [DOI] [PubMed] [Google Scholar]
  42. 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]
  43. 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]
  44. Shinkai Y., Rathbun G., Lam K. P., Oltz E. M., Stewart V., Mendelsohn M., Charron J., Datta M., Young F., Stall A. M. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 1992 Mar 6;68(5):855–867. doi: 10.1016/0092-8674(92)90029-c. [DOI] [PubMed] [Google Scholar]
  45. Sirito M., Lin Q., Maity T., Sawadogo M. Ubiquitous expression of the 43- and 44-kDa forms of transcription factor USF in mammalian cells. Nucleic Acids Res. 1994 Feb 11;22(3):427–433. doi: 10.1093/nar/22.3.427. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Snapper C. M., Zelazowski P., Rosas F. R., Kehry M. R., Tian M., Baltimore D., Sha W. C. B cells from p50/NF-kappa B knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. J Immunol. 1996 Jan 1;156(1):183–191. [PubMed] [Google Scholar]
  47. Tsao B. P., Wang X. F., Peterson C. L., Calame K. In vivo functional analysis of in vitro protein binding sites in the immunoglobulin heavy chain enhancer. Nucleic Acids Res. 1988 Apr 25;16(8):3239–3253. doi: 10.1093/nar/16.8.3239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Urbánek 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. 1994 Dec 2;79(5):901–912. doi: 10.1016/0092-8674(94)90079-5. [DOI] [PubMed] [Google Scholar]
  49. Wenger R. H., Rochelle J. M., Seldin M. F., Köhler G., Nielsen P. J. The heat stable antigen (mouse CD24) gene is differentially regulated but has a housekeeping promoter. J Biol Chem. 1993 Nov 5;268(31):23345–23352. [PubMed] [Google Scholar]
  50. Zhao G. Q., Zhao Q., Zhou X., Mattei M. G., de Crombrugghe B. TFEC, a basic helix-loop-helix protein, forms heterodimers with TFE3 and inhibits TFE3-dependent transcription activation. Mol Cell Biol. 1993 Aug;13(8):4505–4512. doi: 10.1128/mcb.13.8.4505. [DOI] [PMC free article] [PubMed] [Google Scholar]

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