Inhibition of neuronal process outgrowth and neuronal specific gene activation by the Brn-3b transcription factor.
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.
Smith
M D
MD
Department of Molecular Pathology, University College London Medical School, United Kingdom.
Dawson
S J
SJ
Latchman
D S
DS
D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000494:pharmacology*; D019922:GAP-43 Protein; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects*; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D016196:S Phase; D016704:Synapsins / Q000378:metabolism; D016708:Synaptophysin / Q000378:metabolism; D050825:Synaptosomal-Associated Protein 25; D050857:Synaptotagmins; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors / Q000494:pharmacology*
D002135:Calcium-Binding Proteins; D004268:DNA-Binding Proteins; D019922:GAP-43 Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C494188:POU4F1 protein, human; C494190:POU4F2 protein, human; D012333:RNA, Messenger; D016704:Synapsins; D016708:Synaptophysin; D050825:Synaptosomal-Associated Protein 25; D050818:Transcription Factor Brn-3; D050819:Transcription Factor Brn-3A; D050820:Transcription Factor Brn-3B; D014157:Transcription Factors; D050857:Synaptotagmins