Transient CREB-mediated transcription is key in direct neuronal reprogramming.
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.
Ludwig-Maximilians University of Munich, Physiological Genomics, Biomedical Center (BMC), Planegg-Martinsried, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany.
Sergio
S
Gascón
Biochemistry and Molecular Biology Department IV, Faculty of Veterinary Medicine, Complutense University , Madrid, Spain ; Institute of Neurochemistry (IUIN) , Madrid, Spain ; Health Research Institute of the Hospital Clínico San Carlos (IdISSC) , Madrid, Spain.
Felipe
F
Ortega
Ludwig-Maximilians University of Munich, Physiological Genomics, Biomedical Center (BMC), Planegg-Martinsried, Germany; Institute for Stem Cell Research, Helmholtz Center Munich, Neuherberg, Germany; Excellence Cluster of Systems Neurology (SYNERGY), Munich, Germany.
Magdalena
M
Götz
Bcl-2; CREB; Forskolin; ICER; direct reprogramming; immediate early genes; neurogenesis