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

Berwick, Daniel C.; Calissano, Mattia; Corness, Jacqueline D.; Cook, Simon J. and Latchman, David S. (2009). Regulation of Brn-3a N-terminal transcriptional activity by MEK1/2-ERK1/2 signalling in neural differentiation. Brain research, 1256 pp. 8–18.

DOI: https://doi.org/10.1016/j.brainres.2008.12.009

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.

Viewing alternatives

Metrics

Public Attention

Altmetrics from Altmetric

Number of Citations

Citations from Dimensions
No digital document available to download for this item

Item Actions

Export

About

Recommendations