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. 1996 Jun;16(6):2898–2905. doi: 10.1128/mcb.16.6.2898

B-lymphocyte development is regulated by the combined dosage of three basic helix-loop-helix genes, E2A, E2-2, and HEB.

Y Zhuang 1, P Cheng 1, H Weintraub 1
PMCID: PMC231283  PMID: 8649400

Abstract

B-lymphocyte development requires the basic helix-loop-helix proteins encoded by the E2A gene. In this study, the control mechanism of E2A was further explored by disruption of the E2A-related genes, E2-2 and HEB. In contrast to E2A, E2-2 and HEB are not essential for the establishment of the B-cell lineage. However, both E2-2 and HEB are required for the generation of the normal numbers of pro-B cells in mouse embryos. Breeding tests among mice carrying different mutations revealed that E2-2 and HEB interact with E2A in many developmental processes including generation of B cells. Specifically, mice transheterozygous for any two mutations of these three genes produced fewer pro-B cells than the singly heterozygous littermates. This study indicates that B-cell development is dependent not only on an essential function provided by the E2A gene but also on a combined dosage set by E2A, E2-2, and HEB.

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Selected References

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  1. 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]
  2. Benezra R. An intermolecular disulfide bond stabilizes E2A homodimers and is required for DNA binding at physiological temperatures. Cell. 1994 Dec 16;79(6):1057–1067. doi: 10.1016/0092-8674(94)90036-1. [DOI] [PubMed] [Google Scholar]
  3. Benezra R., Davis R. L., Lockshon D., Turner D. L., Weintraub H. The protein Id: a negative regulator of helix-loop-helix DNA binding proteins. Cell. 1990 Apr 6;61(1):49–59. doi: 10.1016/0092-8674(90)90214-y. [DOI] [PubMed] [Google Scholar]
  4. Cline T. W. The affairs of daughterless and the promiscuity of developmental regulators. Cell. 1989 Oct 20;59(2):231–234. doi: 10.1016/0092-8674(89)90280-8. [DOI] [PubMed] [Google Scholar]
  5. Cserjesi P., Brown D., Ligon K. L., Lyons G. E., Copeland N. G., Gilbert D. J., Jenkins N. A., Olson E. N. Scleraxis: a basic helix-loop-helix protein that prefigures skeletal formation during mouse embryogenesis. Development. 1995 Apr;121(4):1099–1110. doi: 10.1242/dev.121.4.1099. [DOI] [PubMed] [Google Scholar]
  6. Genetta T., Ruezinsky D., Kadesch T. Displacement of an E-box-binding repressor by basic helix-loop-helix proteins: implications for B-cell specificity of the immunoglobulin heavy-chain enhancer. Mol Cell Biol. 1994 Sep;14(9):6153–6163. doi: 10.1128/mcb.14.9.6153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Gstaiger M., Knoepfel L., Georgiev O., Schaffner W., Hovens C. M. A B-cell coactivator of octamer-binding transcription factors. Nature. 1995 Jan 26;373(6512):360–362. doi: 10.1038/373360a0. [DOI] [PubMed] [Google Scholar]
  8. Guillemot F., Lo L. C., Johnson J. E., Auerbach A., Anderson D. J., Joyner A. L. Mammalian achaete-scute homolog 1 is required for the early development of olfactory and autonomic neurons. Cell. 1993 Nov 5;75(3):463–476. doi: 10.1016/0092-8674(93)90381-y. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Henthorn P., Kiledjian M., Kadesch T. Two distinct transcription factors that bind the immunoglobulin enhancer microE5/kappa 2 motif. Science. 1990 Jan 26;247(4941):467–470. doi: 10.1126/science.2105528. [DOI] [PubMed] [Google Scholar]
  11. Hu J. S., Olson E. N., Kingston R. E. HEB, a helix-loop-helix protein related to E2A and ITF2 that can modulate the DNA-binding ability of myogenic regulatory factors. Mol Cell Biol. 1992 Mar;12(3):1031–1042. doi: 10.1128/mcb.12.3.1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Jan Y. N., Jan L. Y. HLH proteins, fly neurogenesis, and vertebrate myogenesis. Cell. 1993 Dec 3;75(5):827–830. doi: 10.1016/0092-8674(93)90525-u. [DOI] [PubMed] [Google Scholar]
  13. Kadesch T. Helix-loop-helix proteins in the regulation of immunoglobulin gene transcription. Immunol Today. 1992 Jan;13(1):31–36. doi: 10.1016/0167-5699(92)90201-h. [DOI] [PubMed] [Google Scholar]
  14. Lassar A. B., Davis R. L., Wright W. E., Kadesch T., Murre C., Voronova A., Baltimore D., Weintraub H. Functional activity of myogenic HLH proteins requires hetero-oligomerization with E12/E47-like proteins in vivo. Cell. 1991 Jul 26;66(2):305–315. doi: 10.1016/0092-8674(91)90620-e. [DOI] [PubMed] [Google Scholar]
  15. Luo Y., Roeder R. G. Cloning, functional characterization, and mechanism of action of the B-cell-specific transcriptional coactivator OCA-B. Mol Cell Biol. 1995 Aug;15(8):4115–4124. doi: 10.1128/mcb.15.8.4115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Murre C., McCaw P. S., Vaessin H., Caudy M., Jan L. Y., Jan Y. N., Cabrera C. V., Buskin J. N., Hauschka S. D., Lassar A. B. Interactions between heterologous helix-loop-helix proteins generate complexes that bind specifically to a common DNA sequence. Cell. 1989 Aug 11;58(3):537–544. doi: 10.1016/0092-8674(89)90434-0. [DOI] [PubMed] [Google Scholar]
  17. Nolan G. P., Fiering S., Nicolas J. F., Herzenberg L. A. Fluorescence-activated cell analysis and sorting of viable mammalian cells based on beta-D-galactosidase activity after transduction of Escherichia coli lacZ. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2603–2607. doi: 10.1073/pnas.85.8.2603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Parkhurst S. M., Lipshitz H. D., Ish-Horowicz D. achaete-scute feminizing activities and Drosophila sex determination. Development. 1993 Feb;117(2):737–749. doi: 10.1242/dev.117.2.737. [DOI] [PubMed] [Google Scholar]
  19. Parkhurst S. M., Meneely P. M. Sex determination and dosage compensation: lessons from flies and worms. Science. 1994 May 13;264(5161):924–932. doi: 10.1126/science.8178152. [DOI] [PubMed] [Google Scholar]
  20. 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]
  21. Ruezinsky D., Beckmann H., Kadesch T. Modulation of the IgH enhancer's cell type specificity through a genetic switch. Genes Dev. 1991 Jan;5(1):29–37. doi: 10.1101/gad.5.1.29. [DOI] [PubMed] [Google Scholar]
  22. Sawada S., Littman D. R. A heterodimer of HEB and an E12-related protein interacts with the CD4 enhancer and regulates its activity in T-cell lines. Mol Cell Biol. 1993 Sep;13(9):5620–5628. doi: 10.1128/mcb.13.9.5620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Schlissel M., Voronova A., Baltimore D. Helix-loop-helix transcription factor E47 activates germ-line immunoglobulin heavy-chain gene transcription and rearrangement in a pre-T-cell line. Genes Dev. 1991 Aug;5(8):1367–1376. doi: 10.1101/gad.5.8.1367. [DOI] [PubMed] [Google Scholar]
  24. Shen C. P., Kadesch T. B-cell-specific DNA binding by an E47 homodimer. Mol Cell Biol. 1995 Aug;15(8):4518–4524. doi: 10.1128/mcb.15.8.4518. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Shivdasani R. A., Mayer E. L., Orkin S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature. 1995 Feb 2;373(6513):432–434. doi: 10.1038/373432a0. [DOI] [PubMed] [Google Scholar]
  26. Strubin M., Newell J. W., Matthias P. OBF-1, a novel B cell-specific coactivator that stimulates immunoglobulin promoter activity through association with octamer-binding proteins. Cell. 1995 Feb 10;80(3):497–506. doi: 10.1016/0092-8674(95)90500-6. [DOI] [PubMed] [Google Scholar]
  27. Sun X. H. Constitutive expression of the Id1 gene impairs mouse B cell development. Cell. 1994 Dec 2;79(5):893–900. doi: 10.1016/0092-8674(94)90078-7. [DOI] [PubMed] [Google Scholar]
  28. Sun X. H., Copeland N. G., Jenkins N. A., Baltimore D. Id proteins Id1 and Id2 selectively inhibit DNA binding by one class of helix-loop-helix proteins. Mol Cell Biol. 1991 Nov;11(11):5603–5611. doi: 10.1128/mcb.11.11.5603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Tontonoz P., Kim J. B., Graves R. A., Spiegelman B. M. ADD1: a novel helix-loop-helix transcription factor associated with adipocyte determination and differentiation. Mol Cell Biol. 1993 Aug;13(8):4753–4759. doi: 10.1128/mcb.13.8.4753. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. 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]
  31. Weintraub H., Davis R., Tapscott S., Thayer M., Krause M., Benezra R., Blackwell T. K., Turner D., Rupp R., Hollenberg S. The myoD gene family: nodal point during specification of the muscle cell lineage. Science. 1991 Feb 15;251(4995):761–766. doi: 10.1126/science.1846704. [DOI] [PubMed] [Google Scholar]
  32. Weintraub H., Tapscott S. J., Davis R. L., Thayer M. J., Adam M. A., Lassar A. B., Miller A. D. Activation of muscle-specific genes in pigment, nerve, fat, liver, and fibroblast cell lines by forced expression of MyoD. Proc Natl Acad Sci U S A. 1989 Jul;86(14):5434–5438. doi: 10.1073/pnas.86.14.5434. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Whitlock C. A., Witte O. N. Long-term culture of B lymphocytes and their precursors from murine bone marrow. Proc Natl Acad Sci U S A. 1982 Jun;79(11):3608–3612. doi: 10.1073/pnas.79.11.3608. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Zhuang Y., Soriano P., Weintraub H. The helix-loop-helix gene E2A is required for B cell formation. Cell. 1994 Dec 2;79(5):875–884. doi: 10.1016/0092-8674(94)90076-0. [DOI] [PubMed] [Google Scholar]

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