Cortical Neurogenesis Requires Bcl6-Mediated Transcriptional Repression of Multiple Self-Renewal-Promoting Extrinsic Pathways

Summary 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.
Graphical Abstract
Highlights • Bcl6 ensures robust neurogenesis by repressing major extrinsic self-renewal pathways • Bcl6 inhibits the Notch, Wnt, SHH, and FGF signaling pathways at multiple levels • Bcl6 represses transcription through Sirt1 recruitment and histone deacetylation
Bonnefont et al. show that Bcl6 promotes neurogenesis by directly repressing genes belonging to the major signaling pathways promoting cortical progenitor self-renewal. These data indicate that a single cell-intrinsic factor represses multiple extrinsic signaling pathways to ensure irreversible neurogenic commitment.