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Molecular and Cellular Biology logoLink to Molecular and Cellular Biology
. 1997 Jan;17(1):345–354. doi: 10.1128/mcb.17.1.345

The Brn-3a transcription factor induces neuronal process outgrowth and the coordinate expression of genes encoding synaptic proteins.

M D Smith 1, S J Dawson 1, D S Latchman 1
PMCID: PMC231759  PMID: 8972215

Abstract

The Brn-3a POU family transcription factor is expressed only in posmitotic neurons in the central nervous system and identifies the first differentiated neurons to appear in the midbrain, hindbrain, and spinal cord during development. This factor is also induced when undifferentiated proliferating ND7 cells cease dividing and differentiate to a mature neuronal-like phenotype bearing numerous neurite processes. We show that overexpression of Brn-3a in undifferentiated ND7 cells induces a mature neuronal phenotype characterized by process outgrowth and the induction of genes encoding synaptic proteins, although the cells continue to proliferate. In contrast, the closely related factors Brn-3b and Brn-3c do not have this effect. Although the N-terminal activation domain of Brn-3a is required for maximum induction of neurite outgrowth and gene expression, these effects are primarily dependent on the DNA binding POU domain, which also acts as an activation domain. Overexpression of the isolated POU domain of Brn-3a is sufficient to induce neurite outgrowth, while the ability of full-length Brn-3a to do so is abolished by mutating a single amino acid in the Brn-3a POU homeodomain to its equivalent in Brn-3b. Thus, Brn-3a appears to play a critical role in the specification of the mature neuronal phenotype, acting by stimulating the expression of genes whose products are required for process outgrowth and synapse formation.

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Selected References

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  1. Aigner L., Arber S., Kapfhammer J. P., Laux T., Schneider C., Botteri F., Brenner H. R., Caroni P. Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell. 1995 Oct 20;83(2):269–278. doi: 10.1016/0092-8674(95)90168-x. [DOI] [PubMed] [Google Scholar]
  2. Budhram-Mahadeo V., Morris P. J., Lakin N. D., Theil T., Ching G. Y., Lillycrop K. A., Möröy T., Liem R. K., Latchman D. S. Activation of the alpha-internexin promoter by the Brn-3a transcription factor is dependent on the N-terminal region of the protein. J Biol Chem. 1995 Feb 10;270(6):2853–2858. doi: 10.1074/jbc.270.6.2853. [DOI] [PubMed] [Google Scholar]
  3. Budhram-Mahadeo V., Theil T., Morris P. J., Lillycrop K. A., Moroy T., Latchman D. S. The DNA target site for the Brn-3 POU family transcription factors can confer responsiveness to cyclic AMP and removal of serum in neuronal cells. Nucleic Acids Res. 1994 Aug 11;22(15):3092–3098. doi: 10.1093/nar/22.15.3092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Davis R. L., Weintraub H., Lassar A. B. Expression of a single transfected cDNA converts fibroblasts to myoblasts. Cell. 1987 Dec 24;51(6):987–1000. doi: 10.1016/0092-8674(87)90585-x. [DOI] [PubMed] [Google Scholar]
  5. Dawson S. J., Morris P. J., Latchman D. S. A single amino acid change converts an inhibitory transcription factor into an activator. J Biol Chem. 1996 May 17;271(20):11631–11633. doi: 10.1074/jbc.271.20.11631. [DOI] [PubMed] [Google Scholar]
  6. Dhillon V. B., McCallum S., Norton P., Twomey B. M., Erkeller-Yuksel F., Lydyard P., Isenberg D. A., Latchman D. S. Differential heat shock protein overexpression and its clinical relevance in systemic lupus erythematosus. Ann Rheum Dis. 1993 Jun;52(6):436–442. doi: 10.1136/ard.52.6.436. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Edmondson D. G., Olson E. N. Helix-loop-helix proteins as regulators of muscle-specific transcription. J Biol Chem. 1993 Jan 15;268(2):755–758. [PubMed] [Google Scholar]
  8. Fedtsova N. G., Turner E. E. Brn-3.0 expression identifies early post-mitotic CNS neurons and sensory neural precursors. Mech Dev. 1995 Nov;53(3):291–304. doi: 10.1016/0925-4773(95)00435-1. [DOI] [PubMed] [Google Scholar]
  9. Gerrero M. R., McEvilly R. J., Turner E., Lin C. R., O'Connell S., Jenne K. J., Hobbs M. V., Rosenfeld M. G. Brn-3.0: a POU-domain protein expressed in the sensory, immune, and endocrine systems that functions on elements distinct from known octamer motifs. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10841–10845. doi: 10.1073/pnas.90.22.10841. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. He X., Treacy M. N., Simmons D. M., Ingraham H. A., Swanson L. W., Rosenfeld M. G. Expression of a large family of POU-domain regulatory genes in mammalian brain development. Nature. 1989 Jul 6;340(6228):35–41. doi: 10.1038/340035a0. [DOI] [PubMed] [Google Scholar]
  11. Lakin N. D., Morris P. J., Theil T., Sato T. N., Möröy T., Wilson M. C., Latchman D. S. Regulation of neurite outgrowth and SNAP-25 gene expression by the Brn-3a transcription factor. J Biol Chem. 1995 Jun 30;270(26):15858–15863. doi: 10.1074/jbc.270.26.15858. [DOI] [PubMed] [Google Scholar]
  12. Lillycrop K. A., Budrahan V. S., Lakin N. D., Terrenghi G., Wood J. N., Polak J. M., Latchman D. S. A novel POU family transcription factor is closely related to Brn-3 but has a distinct expression pattern in neuronal cells. Nucleic Acids Res. 1992 Oct 11;20(19):5093–5096. doi: 10.1093/nar/20.19.5093. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Liu Y. Z., Dawson S. J., Latchman D. S. Alternative splicing of the Brn-3a and Brn-3b transcription factor RNAs is regulated in neuronal cells. J Mol Neurosci. 1996 Spring;7(1):77–85. doi: 10.1007/BF02736850. [DOI] [PubMed] [Google Scholar]
  14. Morgenstern J. P., Land H. Advanced mammalian gene transfer: high titre retroviral vectors with multiple drug selection markers and a complementary helper-free packaging cell line. Nucleic Acids Res. 1990 Jun 25;18(12):3587–3596. doi: 10.1093/nar/18.12.3587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Morris P. J., Theil T., Ring C. J., Lillycrop K. A., Moroy T., Latchman D. S. The opposite and antagonistic effects of the closely related POU family transcription factors Brn-3a and Brn-3b on the activity of a target promoter are dependent on differences in the POU domain. Mol Cell Biol. 1994 Oct;14(10):6907–6914. doi: 10.1128/mcb.14.10.6907. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Ninkina N. N., Stevens G. E., Wood J. N., Richardson W. D. A novel Brn3-like POU transcription factor expressed in subsets of rat sensory and spinal cord neurons. Nucleic Acids Res. 1993 Jul 11;21(14):3175–3182. doi: 10.1093/nar/21.14.3175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Osen-Sand A., Catsicas M., Staple J. K., Jones K. A., Ayala G., Knowles J., Grenningloh G., Catsicas S. Inhibition of axonal growth by SNAP-25 antisense oligonucleotides in vitro and in vivo. Nature. 1993 Jul 29;364(6436):445–448. doi: 10.1038/364445a0. [DOI] [PubMed] [Google Scholar]
  18. Oyler G. A., Higgins G. A., Hart R. A., Battenberg E., Billingsley M., Bloom F. E., Wilson M. C. The identification of a novel synaptosomal-associated protein, SNAP-25, differentially expressed by neuronal subpopulations. J Cell Biol. 1989 Dec;109(6 Pt 1):3039–3052. doi: 10.1083/jcb.109.6.3039. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Skene J. H. Axonal growth-associated proteins. Annu Rev Neurosci. 1989;12:127–156. doi: 10.1146/annurev.ne.12.030189.001015. [DOI] [PubMed] [Google Scholar]
  20. Suburo A. M., Wheatley S. C., Horn D. A., Gibson S. J., Jahn R., Fischer-Colbrie R., Wood J. N., Latchman D. S., Polak J. M. Intracellular redistribution of neuropeptides and secretory proteins during differentiation of neuronal cell lines. Neuroscience. 1992;46(4):881–889. doi: 10.1016/0306-4522(92)90191-4. [DOI] [PubMed] [Google Scholar]
  21. Südhof T. C., Jahn R. Proteins of synaptic vesicles involved in exocytosis and membrane recycling. Neuron. 1991 May;6(5):665–677. doi: 10.1016/0896-6273(91)90165-v. [DOI] [PubMed] [Google Scholar]
  22. Südhof T. C. The synaptic vesicle cycle: a cascade of protein-protein interactions. Nature. 1995 Jun 22;375(6533):645–653. doi: 10.1038/375645a0. [DOI] [PubMed] [Google Scholar]
  23. Theil T., McLean-Hunter S., Zörnig M., Möröy T. Mouse Brn-3 family of POU transcription factors: a new aminoterminal domain is crucial for the oncogenic activity of Brn-3a. Nucleic Acids Res. 1993 Dec 25;21(25):5921–5929. doi: 10.1093/nar/21.25.5921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Theil T., Zechner U., Klett C., Adolph S., Möröy T. Chromosomal localization and sequences of the murine Brn-3 family of developmental control genes. Cytogenet Cell Genet. 1994;66(4):267–271. doi: 10.1159/000133709. [DOI] [PubMed] [Google Scholar]
  25. Turner E. E., Jenne K. J., Rosenfeld M. G. Brn-3.2: a Brn-3-related transcription factor with distinctive central nervous system expression and regulation by retinoic acid. Neuron. 1994 Jan;12(1):205–218. doi: 10.1016/0896-6273(94)90164-3. [DOI] [PubMed] [Google Scholar]
  26. Verrijzer C. P., Van der Vliet P. C. POU domain transcription factors. Biochim Biophys Acta. 1993 Apr 29;1173(1):1–21. doi: 10.1016/0167-4781(93)90237-8. [DOI] [PubMed] [Google Scholar]
  27. Wegner M., Drolet D. W., Rosenfeld M. G. POU-domain proteins: structure and function of developmental regulators. Curr Opin Cell Biol. 1993 Jun;5(3):488–498. doi: 10.1016/0955-0674(93)90015-i. [DOI] [PubMed] [Google Scholar]
  28. Wheatley S. C., Suburo A. M., Horn D. A., Vucicevic V., Terenghi G., Polak J. M., Latchman D. S. Redistribution of secretory granule components precedes that of synaptic vesicle proteins during differentiation of a neuronal cell line in serum-free medium. Neuroscience. 1992 Dec;51(3):575–582. doi: 10.1016/0306-4522(92)90297-f. [DOI] [PubMed] [Google Scholar]
  29. Wood J. N., Bevan S. J., Coote P. R., Dunn P. M., Harmar A., Hogan P., Latchman D. S., Morrison C., Rougon G., Theveniau M. Novel cell lines display properties of nociceptive sensory neurons. Proc Biol Sci. 1990 Sep 22;241(1302):187–194. doi: 10.1098/rspb.1990.0084. [DOI] [PubMed] [Google Scholar]

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