Regulation of Brn-3a N-terminal transcriptional activity by MEK1/2-ERK1/2 signalling in neural differentiation.

Abstract

The POU family transcription factor Brn-3a is required for the differentiation and survival of sensory neurones, and is phosphorylated in neuroblastoma cells following treatment with all-trans retinoic acid (RA). Mutation of serines-121 and -122 of Brn-3a to alanine blocks its phosphorylation and impairs RA-mediated neurite outgrowth. Here we show that this deficit in differentiation is mimicked by a single mutation at serine-122, and demonstrate a similar requirement for a second residue, threonine-39. Like Brn-3a, the neuropeptide Galanin has been implicated in the development of sensory neurones. We show that Brn-3a over-expression acts synergistically with RA treatment to up-regulate Galanin promoter activity; that the activity of the N-terminal transcriptional activation domain of Brn-3a is increased following RA treatment; and that both these effects require threonine-39 and serine-122. In addition, we demonstrate that the RA-mediated activation of Galanin promoter activity and Brn-3a N-terminal transcriptional activity are both blocked by pan-MEK inhibitors, and show that the expression of a constitutively-active mutant of MEK1, but not MEK5, is sufficient to increase Brn-3a activity. These results reveal an important role for the ERK1/2 pathway in Brn-3a regulation during RA-mediated neuronal differentiation and define the neuropeptide Galanin as a novel target of this transcription factor.

• Authors: Daniel C Berwick, Mattia Calissano, Jacqueline D Corness, Simon J Cook, David S Latchman
• Journal: Brain research (Brain Res) Vol. 1256 Pg. 8-18 (Feb 23 2009) ISSN: 1872-6240 [Electronic] Netherlands
• PMID: 19135033 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Transcription Factor Brn-3A
• Tretinoin
• Galanin
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• MAP Kinase Kinase 1
• MAP Kinase Kinase 2
• MAP Kinase Kinase 5

Topics

• Animals
• Cell Line
• Galanin (genetics)
• Gene Expression Regulation
• Humans
• MAP Kinase Kinase 1 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 2 (antagonists & inhibitors, metabolism)
• MAP Kinase Kinase 5 (metabolism)
• MAP Kinase Signaling System
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Mutation, Missense
• Neurogenesis (physiology)
• Neurons (cytology, metabolism)
• Promoter Regions, Genetic (drug effects)
• Rats
• Transcription Factor Brn-3A (genetics, metabolism)
• Transcriptional Activation (drug effects, physiology)
• Tretinoin (pharmacology)