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.
Bibliographical noteFunding Information:
We thank G. Vassart for continuous support and interest, D. Christophe and members of the Vanderhaeghen lab and Institute for Interdisciplinary Research for helpful discussions and advice, F. Bollet-Quivogne (Fonds National de la Recherche Scientifique (FNRS) Logistic Scientist) of the Light Microscopy Facility for his support with imaging, R. Dalla-Favera (Columbia University) for generously sharing Bcl6−/− mice, F. Guillemot (National Institute of Medical Research) for kindly providing P19 cells, and G. Del Sal ((Laboratorio Nazionale CIB) Trieste) for the pCS2-N∆E construct, and B. Hassan, A. Soldano and K. De Backer for critically reading the manuscript. This work was funded by grants from the Belgian Queen Elizabeth Medical Foundation, the Fondations Pierre Clerdent and Roger de Spoelberch, the Action de Recherches Concertées Programs, the Interuniversity Attraction Poles Program, Belgian State, Federal Office for Scientific, Technical and Cultural Affairs, the Belgian FNRS and Fonds pour la Recherche Scientifique Médicale, and the Welbio and Programme d’Excellence CIBLES of the Walloon Region (to P.V.), as well as an EMBO Long-Term Fellowship (to L.T.) and a Marie Curie Fellowship (to T.B.). P.V. is Research Director, L.T. Postdoctoral Fellow, and J.v.d.A. and J.P. Research Fellows of the FNRS.