Cortical neurogenesis requires Bcl6-mediated transcriptional repression of multiple self-renewal-promoting extrinsic pathways.

Journal Article: NeuronYear Published: (2019) Volume Number: 103, Article Number: Epub ahead of print

Authors

Bonnefont,Jerome; Tiberi,Luca; van den Ameele,Jelle; Potier,Delphine; Gaber,Zachary B; Lin,Xionghui; Bilheu,Angéline; Herpoel,Adèle; Velez Bravo,Fausto D; Guillemot,François; Aerts,Stein; Vanderhaeghen,Pierre

During neurogenesis, progenitors switch from self-renewal to differentiation through the interplay of intrinsic and extrinsic cues, but how these are integrated remains poorly understood. Here, we combine whole-genome transcriptional and epigenetic analyses with in vivo functional studies to demonstrate that Bcl6, a transcriptional repressor previously reported to promote cortical neurogenesis, acts as a driver of the neurogenic transition through direct silencing of a selective repertoire of genes belonging to multiple extrinsic pathways promoting self-renewal, most strikingly the Wnt pathway. At the molecular level, Bcl6 represses its targets through Sirt1 recruitment followed by histone deacetylation. Our data identify a molecular logic by which a single cell-intrinsic factor represses multiple extrinsic pathways that favor self-renewal, thereby ensuring robustness of neuronal fate transition.