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Inhibition of neuronal process outgrowth and neuronal specific gene activation by the Brn-3b transcription factor.
Department of Molecular Pathology, University College London Medical School, United Kingdom.
The differentiation of the ND7 neuronal cell line to a nondividing phenotype bearing numerous neurite processes is accompanied by a dramatic increase in the levels of the activating POU family transcription factor Brn-3a and a corresponding fall in the levels of the closely related inhibitory factor Brn-3b. We have previously shown that the artificial overexpression of Brn-3a in these cells can induce neurite outgrowth and the activation of genes encoding synaptic vesicle proteins in the absence of a differentiation-inducing stimulus. Here we show that overexpression of Brn-3b can reduce process outgrowth and synaptic vesicle gene expression following exposure to a stimulus which would normally induce differentiation. These inhibitory effects are abolished by altering a single amino acid in the POU homeodomain of Brn-3b to its equivalent in Brn-3a. The converse mutation in Brn-3a allows it to inhibit process outgrowth in response to a differentiation-inducing stimulus. Hence a single amino acid difference results in these closely related factors having opposite effects and allows the balance between them to regulate differentiation.
PMID: 8995448 [PubMed - indexed for MEDLINE]
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Cited by 3 PubMed Central articles
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Identification of the transcriptional targets of FOXP2, a gene linked to speech and language, in developing human brain.
Spiteri E, Konopka G, Coppola G, Bomar J, Oldham M, Ou J, Vernes SC, Fisher SE, Ren B, Geschwind DH.
Am J Hum Genet. 2007 Dec; 81(6):1144-57. Epub 2007 Oct 31.
[Am J Hum Genet. 2007]
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Brn-3b enhances the pro-apoptotic effects of p53 but not its induction of cell cycle arrest by cooperating in trans-activation of bax expression.
Budhram-Mahadeo VS, Bowen S, Lee S, Perez-Sanchez C, Ensor E, Morris PJ, Latchman DS.
Nucleic Acids Res. 2006; 34(22):6640-52. Epub 2006 Dec 1.
[Nucleic Acids Res. 2006]
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The N-terminal domain unique to the long form of the Brn-3a transcription factor is essential to protect neuronal cells from apoptosis and for the activation of Bbcl-2 gene expression.
Smith MD, Dawson SJ, Boxer LM, Latchman DS.
Nucleic Acids Res. 1998 Sep 15; 26(18):4100-7.
[Nucleic Acids Res. 1998]