Transient CREB-mediated transcription is key in direct neuronal reprogramming

Abstract

Combinations of neuronal determinants and/or small-molecules such as Forskolin {(Fk)} can be used to convert different cell types into neurons. As Fk is known to activate {cAMP-dependent} pathways including {CREB-activity,} we aimed here to determine the role of {CREB} in reprogramming - including its temporal profile. We show that transient expression of the dominant-positive {CREB-VP16} followed by its inactivation mediated by the dominant-negative {ICER} improves neuronal conversion of astrocytes mediated by the neurogenic determinant Ascl1. Contrarily, persistent over-activation by {CREB-VP16} or persistent inhibition by {ICER} interferes with neuronal reprogramming, with the latter enhancing cell death. Taken together our work shows transient {CREB} activation as a key effector in neuronal reprogramming.