Author:

Keywords:

Animals, Basic Helix-Loop-Helix Transcription Factors, Cell Differentiation, Cells, Cultured, DNA-Binding Proteins, Embryonic Stem Cells, Epigenetic Repression, Female, Gene Silencing, Gene Targeting, Mice, Mice, Inbred C57BL, Mice, Knockout, Neurogenesis, Pregnancy, Protein Transport, Receptors, Notch, Repressor Proteins, Sirtuin 1, Science & Technology, Life Sciences & Biomedicine, Neurosciences, Neurosciences & Neurology, NEURAL STEM-CELLS, GENE-EXPRESSION, EMBRYONIC STEM, CORTICAL-NEURONS, SIRT1, DIFFERENTIATION, ACTIVATION, IDENTIFICATION, ACETYLATION, CONTRIBUTES, Proto-Oncogene Proteins c-bcl-6, 1109 Neurosciences, 1701 Psychology, 1702 Cognitive Sciences, Neurology & Neurosurgery, 3209 Neurosciences, 5202 Biological psychology

Abstract:

During neurogenesis, neural stem/progenitor cells (NPCs) undergo an irreversible fate transition to become neurons. The Notch pathway is important for this process, and repression of Notch-dependent Hes genes is essential for triggering differentiation. However, Notch signaling often remains active throughout neuronal differentiation, implying a change in the transcriptional responsiveness to Notch during the neurogenic transition. We identified Bcl6, an oncogene, as encoding a proneurogenic factor that is required for proper neurogenesis of the mouse cerebral cortex. BCL6 promoted the neurogenic conversion by switching the composition of Notch-dependent transcriptional complexes at the Hes5 promoter. BCL6 triggered exclusion of the co-activator Mastermind-like 1 and recruitment of the NAD(+)-dependent deacetylase Sirt1, which was required for BCL6-dependent neurogenesis. The resulting epigenetic silencing of Hes5 led to neuronal differentiation despite active Notch signaling. Our findings suggest a role for BCL6 in neurogenesis and uncover Notch-BCL6-Sirt1 interactions that may affect other aspects of physiology and disease.