Abstract
Previous work (6-10) has shown that allelic exclusion of Ig gene expression is controlled by functionally rearranged mu and kappa genes. This report deals with the comparison of membrane mu (micron) and secreted mu (microsecond) in promoting such feedback inhibition. Splenic B cell hybridomas were analyzed from transgenic mice harboring a rearranged kappa gene alone or in combination with either an intact rearranged mu gene or a truncated version of the mu gene. The intact mu gene is capable of producing both membrane and secreted forms of the protein, while the truncated version can only encode the secreted form. The role of the microsecond was also tested in pre-B cell lines. Analysis of the extent of endogenous Ig gene rearrangement revealed that (a) the production of micron together with kappa can terminate Ig gene rearrangement; (b) microsecond with kappa does not have this feedback effect; (c) microsecond may interfere with the effect of micron and kappa; and (d) the feedback shown here probably represents a complete shutoff of the specific recombinase by micron + kappa; the data do not address the question of mu alone affecting the accessibility of H genes for rearrangement.
Full Text
The Full Text of this article is available as a PDF (1.6 MB).
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- Alt F. W., Blackwell T. K., DePinho R. A., Reth M. G., Yancopoulos G. D. Regulation of genome rearrangement events during lymphocyte differentiation. Immunol Rev. 1986 Feb;89:5–30. doi: 10.1111/j.1600-065x.1986.tb01470.x. [DOI] [PubMed] [Google Scholar]
- Alt F. W., Yancopoulos G. D., Blackwell T. K., Wood C., Thomas E., Boss M., Coffman R., Rosenberg N., Tonegawa S., Baltimore D. Ordered rearrangement of immunoglobulin heavy chain variable region segments. EMBO J. 1984 Jun;3(6):1209–1219. doi: 10.1002/j.1460-2075.1984.tb01955.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Blackwell T. K., Alt F. W. Site-specific recombination between immunoglobulin D and JH segments that were introduced into the genome of a murine pre-B cell line. Cell. 1984 May;37(1):105–112. doi: 10.1016/0092-8674(84)90305-2. [DOI] [PubMed] [Google Scholar]
- Brinster R. L., Chen H. Y., Trumbauer M. E. Mouse oocytes transcribe injected Xenopus 5S RNA gene. Science. 1981 Jan 23;211(4480):396–398. doi: 10.1126/science.7194505. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brinster R. L., Chen H. Y., Trumbauer M. E., Yagle M. K., Palmiter R. D. Factors affecting the efficiency of introducing foreign DNA into mice by microinjecting eggs. Proc Natl Acad Sci U S A. 1985 Jul;82(13):4438–4442. doi: 10.1073/pnas.82.13.4438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Cebra J. J., Colberg J. E., Dray S. Rabbit lymphoid cells differentiated with respect to alpha-, gamma-, and mu- heavy polypeptide chains and to allotypic markers Aa1 and Aa2. J Exp Med. 1966 Mar 1;123(3):547–558. doi: 10.1084/jem.123.3.547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Early P., Rogers J., Davis M., Calame K., Bond M., Wall R., Hood L. Two mRNAs can be produced from a single immunoglobulin mu gene by alternative RNA processing pathways. Cell. 1980 Jun;20(2):313–319. doi: 10.1016/0092-8674(80)90617-0. [DOI] [PubMed] [Google Scholar]
- Engler P., Storb U. High-frequency deletional rearrangement of immunoglobulin kappa gene segments introduced into a pre-B-cell line. Proc Natl Acad Sci U S A. 1987 Jul;84(14):4949–4953. doi: 10.1073/pnas.84.14.4949. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Feddersen R. M., Van Ness B. G. Double recombination of a single immunoglobulin kappa-chain allele: implications for the mechanism of rearrangement. Proc Natl Acad Sci U S A. 1985 Jul;82(14):4793–4797. doi: 10.1073/pnas.82.14.4793. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Galli G., Guise J. W., McDevitt M. A., Tucker P. W., Nevins J. R. Relative position and strengths of poly(A) sites as well as transcription termination are critical to membrane versus secreted mu-chain expression during B-cell development. Genes Dev. 1987 Jul;1(5):471–481. doi: 10.1101/gad.1.5.471. [DOI] [PubMed] [Google Scholar]
- Hardy R. R., Dangl J. L., Hayakawa K., Jager G., Herzenberg L. A., Herzenberg L. A. Frequent lambda light chain gene rearrangement and expression in a Ly-1 B lymphoma with a productive kappa chain allele. Proc Natl Acad Sci U S A. 1986 Mar;83(5):1438–1442. doi: 10.1073/pnas.83.5.1438. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hayakawa K., Hardy R. R., Herzenberg L. A., Herzenberg L. A. Progenitors for Ly-1 B cells are distinct from progenitors for other B cells. J Exp Med. 1985 Jun 1;161(6):1554–1568. doi: 10.1084/jem.161.6.1554. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Iglesias A., Lamers M., Köhler G. Expression of immunoglobulin delta chain causes allelic exclusion in transgenic mice. Nature. 1987 Dec 3;330(6147):482–484. doi: 10.1038/330482a0. [DOI] [PubMed] [Google Scholar]
- Kearney J. F., Radbruch A., Liesegang B., Rajewsky K. A new mouse myeloma cell line that has lost immunoglobulin expression but permits the construction of antibody-secreting hybrid cell lines. J Immunol. 1979 Oct;123(4):1548–1550. [PubMed] [Google Scholar]
- Kelley D. E., Perry R. P. Transcriptional and posttranscriptional control of immunoglobulin mRNA production during B lymphocyte development. Nucleic Acids Res. 1986 Jul 11;14(13):5431–5447. doi: 10.1093/nar/14.13.5431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kemp D. J., Harris A. W., Adams J. M. Transcripts of the immunoglobulin C mu gene vary in structure and splicing during lymphoid development. Proc Natl Acad Sci U S A. 1980 Dec;77(12):7400–7404. doi: 10.1073/pnas.77.12.7400. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kim S., Davis M., Sinn E., Patten P., Hood L. Antibody diversity: somatic hypermutation of rearranged VH genes. Cell. 1981 Dec;27(3 Pt 2):573–581. doi: 10.1016/0092-8674(81)90399-8. [DOI] [PubMed] [Google Scholar]
- Kincade P. W., Lee G., Sun L., Watanabe T. Monoclonal rat antibodies to murine IgM determinants. J Immunol Methods. 1981;42(1):17–26. doi: 10.1016/0022-1759(81)90220-9. [DOI] [PubMed] [Google Scholar]
- Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
- Lewis S., Gifford A., Baltimore D. Joining of V kappa to J kappa gene segments in a retroviral vector introduced into lymphoid cells. 1984 Mar 29-Apr 4Nature. 308(5958):425–428. doi: 10.1038/308425a0. [DOI] [PubMed] [Google Scholar]
- Lieber M. R., Hesse J. E., Mizuuchi K., Gellert M. Developmental stage specificity of the lymphoid V(D)J recombination activity. Genes Dev. 1987 Oct;1(8):751–761. doi: 10.1101/gad.1.8.751. [DOI] [PubMed] [Google Scholar]
- Marcu K. B., Banerji J., Penncavage N. A., Lang R., Arnheim N. 5' flanking region of immunoglobulin heavy chain constant region genes displays length heterogeneity in germlines of inbred mouse strains. Cell. 1980 Nov;22(1 Pt 1):187–196. doi: 10.1016/0092-8674(80)90167-1. [DOI] [PubMed] [Google Scholar]
- Nelson K. J., Haimovich J., Perry R. P. Characterization of productive and sterile transcripts from the immunoglobulin heavy-chain locus: processing of micron and muS mRNA. Mol Cell Biol. 1983 Jul;3(7):1317–1332. doi: 10.1128/mcb.3.7.1317. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nowinski R. C., Lostrom M. E., Tam M. R., Stone M. R., Burnette W. N. The isolation of hybrid cell lines producing monoclonal antibodies against the p15(E) protein of ecotropic murine leukemia viruses. Virology. 1979 Feb;93(1):111–126. doi: 10.1016/0042-6822(79)90280-0. [DOI] [PubMed] [Google Scholar]
- Nussenzweig M. C., Shaw A. C., Sinn E., Danner D. B., Holmes K. L., Morse H. C., 3rd, Leder P. Allelic exclusion in transgenic mice that express the membrane form of immunoglobulin mu. Science. 1987 May 15;236(4803):816–819. doi: 10.1126/science.3107126. [DOI] [PubMed] [Google Scholar]
- O'Brien R. L., Brinster R. L., Storb U. Somatic hypermutation of an immunoglobulin transgene in kappa transgenic mice. 1987 Mar 26-Apr 1Nature. 326(6111):405–409. doi: 10.1038/326405a0. [DOI] [PubMed] [Google Scholar]
- Pernis B., Chiappino G., Kelus A. S., Gell P. G. Cellular localization of immunoglobulins with different allotypic specificities in rabbit lymphoid tissues. J Exp Med. 1965 Nov 1;122(5):853–876. doi: 10.1084/jem.122.5.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reth M., Petrac E., Wiese P., Lobel L., Alt F. W. Activation of V kappa gene rearrangement in pre-B cells follows the expression of membrane-bound immunoglobulin heavy chains. EMBO J. 1987 Nov;6(11):3299–3305. doi: 10.1002/j.1460-2075.1987.tb02649.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Ritchie K. A., Brinster R. L., Storb U. Allelic exclusion and control of endogenous immunoglobulin gene rearrangement in kappa transgenic mice. Nature. 1984 Dec 6;312(5994):517–520. doi: 10.1038/312517a0. [DOI] [PubMed] [Google Scholar]
- Rogers J., Early P., Carter C., Calame K., Bond M., Hood L., Wall R. Two mRNAs with different 3' ends encode membrane-bound and secreted forms of immunoglobulin mu chain. Cell. 1980 Jun;20(2):303–312. doi: 10.1016/0092-8674(80)90616-9. [DOI] [PubMed] [Google Scholar]
- Rusconi S., Köhler G. Transmission and expression of a specific pair of rearranged immunoglobulin mu and kappa genes in a transgenic mouse line. 1985 Mar 28-Apr 3Nature. 314(6009):330–334. doi: 10.1038/314330a0. [DOI] [PubMed] [Google Scholar]
- Selsing E., Storb U. Somatic mutation of immunoglobulin light-chain variable-region genes. Cell. 1981 Jul;25(1):47–58. doi: 10.1016/0092-8674(81)90230-0. [DOI] [PubMed] [Google Scholar]
- Selsing E., Voss J., Storb U. Immunoglobulin gene 'remnant' DNA--implications for antibody gene recombination. Nucleic Acids Res. 1984 May 25;12(10):4229–4246. doi: 10.1093/nar/12.10.4229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Shapiro M. A., Weigert M. How immunoglobulin V kappa genes rearrange. J Immunol. 1987 Dec 1;139(11):3834–3839. [PubMed] [Google Scholar]
- Southern E. M. Detection of specific sequences among DNA fragments separated by gel electrophoresis. J Mol Biol. 1975 Nov 5;98(3):503–517. doi: 10.1016/s0022-2836(75)80083-0. [DOI] [PubMed] [Google Scholar]
- Stall A. M., Loken M. R. Allotypic specificities of murine IgD and IgM recognized by monoclonal antibodies. J Immunol. 1984 Feb;132(2):787–795. [PubMed] [Google Scholar]
- Storb U., Denis K. A., Brinster R. L., Witte O. N. Pre-B cells in kappa-transgenic mice. Nature. 1985 Jul 25;316(6026):356–358. doi: 10.1038/316356a0. [DOI] [PubMed] [Google Scholar]
- Storb U., Pinkert C., Arp B., Engler P., Gollahon K., Manz J., Brady W., Brinster R. L. Transgenic mice with mu and kappa genes encoding antiphosphorylcholine antibodies. J Exp Med. 1986 Aug 1;164(2):627–641. doi: 10.1084/jem.164.2.627. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Storb U., Ritchie K. A., O'Brien R., Arp B., Brinster R. Expression, allelic exclusion and somatic mutation of mouse immunoglobulin kappa genes. Immunol Rev. 1986 Feb;89:85–102. doi: 10.1111/j.1600-065x.1986.tb01474.x. [DOI] [PubMed] [Google Scholar]
- Storb U. Transgenic mice with immunoglobulin genes. Annu Rev Immunol. 1987;5:151–174. doi: 10.1146/annurev.iy.05.040187.001055. [DOI] [PubMed] [Google Scholar]
- Towbin H., Staehelin T., Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci U S A. 1979 Sep;76(9):4350–4354. doi: 10.1073/pnas.76.9.4350. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tsang H., Pinkert C., Hagman J., Lostrum M., Brinster R. L., Storb U. Cloning of a gamma 2b gene encoding anti-Pseudomonas aeruginosa H chains and its introduction into the germ line of mice. J Immunol. 1988 Jul 1;141(1):308–314. [PubMed] [Google Scholar]
- Weaver D., Costantini F., Imanishi-Kari T., Baltimore D. A transgenic immunoglobulin mu gene prevents rearrangement of endogenous genes. Cell. 1985 Aug;42(1):117–127. doi: 10.1016/s0092-8674(85)80107-0. [DOI] [PubMed] [Google Scholar]
- Whitlock C. A., Ziegler S. F., Treiman L. J., Stafford J. I., Witte O. N. Differentiation of cloned populations of immature B cells after transformation with Abelson murine leukemia virus. Cell. 1983 Mar;32(3):903–911. doi: 10.1016/0092-8674(83)90075-2. [DOI] [PubMed] [Google Scholar]
- Wilson R., Miller J., Storb U. Rearrangement of immunoglobulin genes. Biochemistry. 1979 Oct 30;18(22):5013–5021. doi: 10.1021/bi00589a032. [DOI] [PubMed] [Google Scholar]
- Yancopoulos G. D., Alt F. W. Developmentally controlled and tissue-specific expression of unrearranged VH gene segments. Cell. 1985 Feb;40(2):271–281. doi: 10.1016/0092-8674(85)90141-2. [DOI] [PubMed] [Google Scholar]
- Yancopoulos G. D., Blackwell T. K., Suh H., Hood L., Alt F. W. Introduced T cell receptor variable region gene segments recombine in pre-B cells: evidence that B and T cells use a common recombinase. Cell. 1986 Jan 31;44(2):251–259. doi: 10.1016/0092-8674(86)90759-2. [DOI] [PubMed] [Google Scholar]
- Yoshida N., Radbruch A., Rajewsky K. Ig gene rearrangement and expression in the progeny of B-cell progenitors in the course of clonal expansion in bone marrow cultures. EMBO J. 1987 Sep;6(9):2735–2741. doi: 10.1002/j.1460-2075.1987.tb02567.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yuan D., Witte P. L. Transcriptional regulation of mu and delta gene expression in bone marrow pre-B and B lymphocytes. J Immunol. 1988 Apr 15;140(8):2808–2814. [PubMed] [Google Scholar]