Skip to main content
NCBI home page
The EMBO Journal logoLink to The EMBO Journal
. 1992 Jul;11(7):2551–2561. doi: 10.1002/j.1460-2075.1992.tb05320.x

Brain 4: a novel mammalian POU domain transcription factor exhibiting restricted brain-specific expression.

J M Mathis 1, D M Simmons 1, X He 1, L W Swanson 1, M G Rosenfeld 1
PMCID: PMC556730  PMID: 1628619

Abstract

The POU domain gene family of transcription factors share a conserved bipartite DNA binding domain, and exhibit distinct temporal and spatial patterns of expression during development, particularly in the forebrain. A cDNA encoding a new member of the POU-III class of the POU domain gene family, referred to as Brn-4, was isolated from a rat hypothalamic cDNA library. Like other mammalian POU-III genes previously characterized (Brn-1, Brn-2, Tst-1), Brn-4 transcripts are initially widely expressed at all levels of the developing neural tube, but in contrast to other previously described POU-III genes, are subsequently restricted to only a few regions of the adult forebrain, including the supraoptic and paraventricular nuclei of the hypothalamus. Brn-4 was shown to bind to DNA sequences containing the octamer motif and to trans-activate promoters containing this DNA binding motif, based on the actions of a unique N-terminal information. This ontogenic pattern of Brn-4 expression in concert with that of Oct-2 and Pit-1, indicates that certain POU domain genes potentially exert their primary functions widely during early neural development, and in a very limited set of neurons in the mature brain.

Full text

PDF
2551

Images in this article

2552Image
on p.2552
2553Image
on p.2553
2554Image
on p.2554
2555Image
on p.2555
2555Image
on p.2555
2556Image
on p.2556
2556Image
on p.2556
2557Image
on p.2557

Selected References

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

  1. Agarwal V. R., Sato S. M. XLPOU 1 and XLPOU 2, two novel POU domain genes expressed in the dorsoanterior region of Xenopus embryos. Dev Biol. 1991 Oct;147(2):363–373. doi: 10.1016/0012-1606(91)90294-d. [DOI] [PubMed] [Google Scholar]
  2. Beachy P. A., Krasnow M. A., Gavis E. R., Hogness D. S. An Ultrabithorax protein binds sequences near its own and the Antennapedia P1 promoters. Cell. 1988 Dec 23;55(6):1069–1081. doi: 10.1016/0092-8674(88)90251-6. [DOI] [PubMed] [Google Scholar]
  3. Carrasco A. E., McGinnis W., Gehring W. J., De Robertis E. M. Cloning of an X. laevis gene expressed during early embryogenesis coding for a peptide region homologous to Drosophila homeotic genes. Cell. 1984 Jun;37(2):409–414. doi: 10.1016/0092-8674(84)90371-4. [DOI] [PubMed] [Google Scholar]
  4. Chen C., Okayama H. High-efficiency transformation of mammalian cells by plasmid DNA. Mol Cell Biol. 1987 Aug;7(8):2745–2752. doi: 10.1128/mcb.7.8.2745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  6. Chisaka O., Capecchi M. R. Regionally restricted developmental defects resulting from targeted disruption of the mouse homeobox gene hox-1.5. Nature. 1991 Apr 11;350(6318):473–479. doi: 10.1038/350473a0. [DOI] [PubMed] [Google Scholar]
  7. Clerc R. G., Corcoran L. M., LeBowitz J. H., Baltimore D., Sharp P. A. The B-cell-specific Oct-2 protein contains POU box- and homeo box-type domains. Genes Dev. 1988 Dec;2(12A):1570–1581. doi: 10.1101/gad.2.12a.1570. [DOI] [PubMed] [Google Scholar]
  8. Desplan C., Theis J., O'Farrell P. H. The sequence specificity of homeodomain-DNA interaction. Cell. 1988 Sep 23;54(7):1081–1090. doi: 10.1016/0092-8674(88)90123-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Elsholtz H. P., Albert V. R., Treacy M. N., Rosenfeld M. G. A two-base change in a POU factor-binding site switches pituitary-specific to lymphoid-specific gene expression. Genes Dev. 1990 Jan;4(1):43–51. doi: 10.1101/gad.4.1.43. [DOI] [PubMed] [Google Scholar]
  10. Emeson R. B., Hedjran F., Yeakley J. M., Guise J. W., Rosenfeld M. G. Alternative production of calcitonin and CGRP mRNA is regulated at the calcitonin-specific splice acceptor. Nature. 1989 Sep 7;341(6237):76–80. doi: 10.1038/341076a0. [DOI] [PubMed] [Google Scholar]
  11. Feinberg A. P., Vogelstein B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal Biochem. 1983 Jul 1;132(1):6–13. doi: 10.1016/0003-2697(83)90418-9. [DOI] [PubMed] [Google Scholar]
  12. Finney M., Ruvkun G. The unc-86 gene product couples cell lineage and cell identity in C. elegans. Cell. 1990 Nov 30;63(5):895–905. doi: 10.1016/0092-8674(90)90493-x. [DOI] [PubMed] [Google Scholar]
  13. Garner M. M., Revzin A. A gel electrophoresis method for quantifying the binding of proteins to specific DNA regions: application to components of the Escherichia coli lactose operon regulatory system. Nucleic Acids Res. 1981 Jul 10;9(13):3047–3060. doi: 10.1093/nar/9.13.3047. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gehring W. J. Homeo boxes in the study of development. Science. 1987 Jun 5;236(4806):1245–1252. doi: 10.1126/science.2884726. [DOI] [PubMed] [Google Scholar]
  15. Glass C. K., Holloway J. M., Devary O. V., Rosenfeld M. G. The thyroid hormone receptor binds with opposite transcriptional effects to a common sequence motif in thyroid hormone and estrogen response elements. Cell. 1988 Jul 29;54(3):313–323. doi: 10.1016/0092-8674(88)90194-8. [DOI] [PubMed] [Google Scholar]
  16. Hara Y., Rovescalli A. C., Kim Y., Nirenberg M. Structure and evolution of four POU domain genes expressed in mouse brain. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3280–3284. doi: 10.1073/pnas.89.8.3280. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. He X., Gerrero R., Simmons D. M., Park R. E., Lin C. J., Swanson L. W., Rosenfeld M. G. Tst-1, a member of the POU domain gene family, binds the promoter of the gene encoding the cell surface adhesion molecule P0. Mol Cell Biol. 1991 Mar;11(3):1739–1744. doi: 10.1128/mcb.11.3.1739. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hoey T., Levine M. Divergent homeo box proteins recognize similar DNA sequences in Drosophila. Nature. 1988 Apr 28;332(6167):858–861. doi: 10.1038/332858a0. [DOI] [PubMed] [Google Scholar]
  19. Holland P. W., Hogan B. L. Expression of homeo box genes during mouse development: a review. Genes Dev. 1988 Jul;2(7):773–782. doi: 10.1101/gad.2.7.773. [DOI] [PubMed] [Google Scholar]
  20. Ingham P. W. The molecular genetics of embryonic pattern formation in Drosophila. Nature. 1988 Sep 1;335(6185):25–34. doi: 10.1038/335025a0. [DOI] [PubMed] [Google Scholar]
  21. Ingraham H. A., Chen R. P., Mangalam H. J., Elsholtz H. P., Flynn S. E., Lin C. R., Simmons D. M., Swanson L., Rosenfeld M. G. A tissue-specific transcription factor containing a homeodomain specifies a pituitary phenotype. Cell. 1988 Nov 4;55(3):519–529. doi: 10.1016/0092-8674(88)90038-4. [DOI] [PubMed] [Google Scholar]
  22. Ingraham H. A., Flynn S. E., Voss J. W., Albert V. R., Kapiloff M. S., Wilson L., Rosenfeld M. G. The POU-specific domain of Pit-1 is essential for sequence-specific, high affinity DNA binding and DNA-dependent Pit-1-Pit-1 interactions. Cell. 1990 Jun 15;61(6):1021–1033. doi: 10.1016/0092-8674(90)90067-o. [DOI] [PubMed] [Google Scholar]
  23. Jaynes J. B., O'Farrell P. H. Activation and repression of transcription by homoeodomain-containing proteins that bind a common site. Nature. 1988 Dec 22;336(6201):744–749. doi: 10.1038/336744a0. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Kemler I., Schaffner W. Octamer transcription factors and the cell type-specificity of immunoglobulin gene expression. FASEB J. 1990 Mar;4(5):1444–1449. doi: 10.1096/fasebj.4.5.2407588. [DOI] [PubMed] [Google Scholar]
  25. Kessel M., Gruss P. Murine developmental control genes. Science. 1990 Jul 27;249(4967):374–379. doi: 10.1126/science.1974085. [DOI] [PubMed] [Google Scholar]
  26. Ko H. S., Fast P., McBride W., Staudt L. M. A human protein specific for the immunoglobulin octamer DNA motif contains a functional homeobox domain. Cell. 1988 Oct 7;55(1):135–144. doi: 10.1016/0092-8674(88)90016-5. [DOI] [PubMed] [Google Scholar]
  27. Kristie T. M., LeBowitz J. H., Sharp P. A. The octamer-binding proteins form multi-protein--DNA complexes with the HSV alpha TIF regulatory protein. EMBO J. 1989 Dec 20;8(13):4229–4238. doi: 10.1002/j.1460-2075.1989.tb08608.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Kristie T. M., Sharp P. A. Interactions of the Oct-1 POU subdomains with specific DNA sequences and with the HSV alpha-trans-activator protein. Genes Dev. 1990 Dec;4(12B):2383–2396. doi: 10.1101/gad.4.12b.2383. [DOI] [PubMed] [Google Scholar]
  29. Kuhn R., Monuki E. S., Lemke G. The gene encoding the transcription factor SCIP has features of an expressed retroposon. Mol Cell Biol. 1991 Sep;11(9):4642–4650. doi: 10.1128/mcb.11.9.4642. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Le Moine C., Young W. S., 3rd RHS2, a POU domain-containing gene, and its expression in developing and adult rat. Proc Natl Acad Sci U S A. 1992 Apr 15;89(8):3285–3289. doi: 10.1073/pnas.89.8.3285. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. LeBowitz J. H., Clerc R. G., Brenowitz M., Sharp P. A. The Oct-2 protein binds cooperatively to adjacent octamer sites. Genes Dev. 1989 Oct;3(10):1625–1638. doi: 10.1101/gad.3.10.1625. [DOI] [PubMed] [Google Scholar]
  32. Lemke G., Lamar E., Patterson J. Isolation and analysis of the gene encoding peripheral myelin protein zero. Neuron. 1988 Mar;1(1):73–83. doi: 10.1016/0896-6273(88)90211-5. [DOI] [PubMed] [Google Scholar]
  33. Li S., Crenshaw E. B., 3rd, Rawson E. J., Simmons D. M., Swanson L. W., Rosenfeld M. G. Dwarf locus mutants lacking three pituitary cell types result from mutations in the POU-domain gene pit-1. Nature. 1990 Oct 11;347(6293):528–533. doi: 10.1038/347528a0. [DOI] [PubMed] [Google Scholar]
  34. Lufkin T., Dierich A., LeMeur M., Mark M., Chambon P. Disruption of the Hox-1.6 homeobox gene results in defects in a region corresponding to its rostral domain of expression. Cell. 1991 Sep 20;66(6):1105–1119. doi: 10.1016/0092-8674(91)90034-v. [DOI] [PubMed] [Google Scholar]
  35. Mangalam H. J., Albert V. R., Ingraham H. A., Kapiloff M., Wilson L., Nelson C., Elsholtz H., Rosenfeld M. G. A pituitary POU domain protein, Pit-1, activates both growth hormone and prolactin promoters transcriptionally. Genes Dev. 1989 Jul;3(7):946–958. doi: 10.1101/gad.3.7.946. [DOI] [PubMed] [Google Scholar]
  36. McGinnis W., Levine M. S., Hafen E., Kuroiwa A., Gehring W. J. A conserved DNA sequence in homoeotic genes of the Drosophila Antennapedia and bithorax complexes. 1984 Mar 29-Apr 4Nature. 308(5958):428–433. doi: 10.1038/308428a0. [DOI] [PubMed] [Google Scholar]
  37. Meijer D., Graus A., Kraay R., Langeveld A., Mulder M. P., Grosveld G. The octamer binding factor Oct6: cDNA cloning and expression in early embryonic cells. Nucleic Acids Res. 1990 Dec 25;18(24):7357–7365. doi: 10.1093/nar/18.24.7357. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Murre C., McCaw P. S., Baltimore D. A new DNA binding and dimerization motif in immunoglobulin enhancer binding, daughterless, MyoD, and myc proteins. Cell. 1989 Mar 10;56(5):777–783. doi: 10.1016/0092-8674(89)90682-x. [DOI] [PubMed] [Google Scholar]
  39. Poellinger L., Yoza B. K., Roeder R. G. Functional cooperativity between protein molecules bound at two distinct sequence elements of the immunoglobulin heavy-chain promoter. Nature. 1989 Feb 9;337(6207):573–576. doi: 10.1038/337573a0. [DOI] [PubMed] [Google Scholar]
  40. Rosenfeld M. G. POU-domain transcription factors: pou-er-ful developmental regulators. Genes Dev. 1991 Jun;5(6):897–907. doi: 10.1101/gad.5.6.897. [DOI] [PubMed] [Google Scholar]
  41. Ruvkun G., Finney M. Regulation of transcription and cell identity by POU domain proteins. Cell. 1991 Feb 8;64(3):475–478. doi: 10.1016/0092-8674(91)90227-p. [DOI] [PubMed] [Google Scholar]
  42. Sanger F., Nicklen S., Coulson A. R. DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci U S A. 1977 Dec;74(12):5463–5467. doi: 10.1073/pnas.74.12.5463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Schöler H. R., Hatzopoulos A. K., Balling R., Suzuki N., Gruss P. A family of octamer-specific proteins present during mouse embryogenesis: evidence for germline-specific expression of an Oct factor. EMBO J. 1989 Sep;8(9):2543–2550. doi: 10.1002/j.1460-2075.1989.tb08392.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Schöler H. R. Octamania: the POU factors in murine development. Trends Genet. 1991 Oct;7(10):323–329. doi: 10.1016/0168-9525(91)90422-m. [DOI] [PubMed] [Google Scholar]
  45. Scott M. P., Carroll S. B. The segmentation and homeotic gene network in early Drosophila development. Cell. 1987 Dec 4;51(5):689–698. doi: 10.1016/0092-8674(87)90092-4. [DOI] [PubMed] [Google Scholar]
  46. Scott M. P., Tamkun J. W., Hartzell G. W., 3rd The structure and function of the homeodomain. Biochim Biophys Acta. 1989 Jul 28;989(1):25–48. doi: 10.1016/0304-419x(89)90033-4. [DOI] [PubMed] [Google Scholar]
  47. Scott M. P., Weiner A. J. Structural relationships among genes that control development: sequence homology between the Antennapedia, Ultrabithorax, and fushi tarazu loci of Drosophila. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4115–4119. doi: 10.1073/pnas.81.13.4115. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Simmons D. M., Voss J. W., Ingraham H. A., Holloway J. M., Broide R. S., Rosenfeld M. G., Swanson L. W. Pituitary cell phenotypes involve cell-specific Pit-1 mRNA translation and synergistic interactions with other classes of transcription factors. Genes Dev. 1990 May;4(5):695–711. doi: 10.1101/gad.4.5.695. [DOI] [PubMed] [Google Scholar]
  49. 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]
  50. Studier F. W., Moffatt B. A. Use of bacteriophage T7 RNA polymerase to direct selective high-level expression of cloned genes. J Mol Biol. 1986 May 5;189(1):113–130. doi: 10.1016/0022-2836(86)90385-2. [DOI] [PubMed] [Google Scholar]
  51. Sturm R. A., Das G., Herr W. The ubiquitous octamer-binding protein Oct-1 contains a POU domain with a homeo box subdomain. Genes Dev. 1988 Dec;2(12A):1582–1599. doi: 10.1101/gad.2.12a.1582. [DOI] [PubMed] [Google Scholar]
  52. Thompson R. C., Seasholtz A. F., Herbert E. Rat corticotropin-releasing hormone gene: sequence and tissue-specific expression. Mol Endocrinol. 1987 May;1(5):363–370. doi: 10.1210/mend-1-5-363. [DOI] [PubMed] [Google Scholar]
  53. Treacy M. N., He X., Rosenfeld M. G. I-POU: a POU-domain protein that inhibits neuron-specific gene activation. Nature. 1991 Apr 18;350(6319):577–584. doi: 10.1038/350577a0. [DOI] [PubMed] [Google Scholar]
  54. Verrijzer C. P., Kal A. J., Van der Vliet P. C. The DNA binding domain (POU domain) of transcription factor oct-1 suffices for stimulation of DNA replication. EMBO J. 1990 Jun;9(6):1883–1888. doi: 10.1002/j.1460-2075.1990.tb08314.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Verrijzer C. P., Kal A. J., van der Vliet P. C. The oct-1 homeo domain contacts only part of the octamer sequence and full oct-1 DNA-binding activity requires the POU-specific domain. Genes Dev. 1990 Nov;4(11):1964–1974. doi: 10.1101/gad.4.11.1964. [DOI] [PubMed] [Google Scholar]
  56. Verrijzer C. P., van Oosterhout J. A., van der Vliet P. C. The Oct-1 POU domain mediates interactions between Oct-1 and other POU proteins. Mol Cell Biol. 1992 Feb;12(2):542–551. doi: 10.1128/mcb.12.2.542. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Voss J. W., Wilson L., Rosenfeld M. G. POU-domain proteins Pit-1 and Oct-1 interact to form a heteromeric complex and can cooperate to induce expression of the prolactin promoter. Genes Dev. 1991 Jul;5(7):1309–1320. doi: 10.1101/gad.5.7.1309. [DOI] [PubMed] [Google Scholar]
  58. Wirth T., Staudt L., Baltimore D. An octamer oligonucleotide upstream of a TATA motif is sufficient for lymphoid-specific promoter activity. Nature. 1987 Sep 10;329(6135):174–178. doi: 10.1038/329174a0. [DOI] [PubMed] [Google Scholar]

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

RESOURCES