[P1.63]: Feedback in the developing neocortex: Neurons control cell fate of progenitors

The coordinate regulation of many aspects of the neurogenic differentiation program is controlled, to large extent, by basic helix-loop-helix (bHLH) transcription factors encoded by so called proneural genes. In spite of the wealth of information on their cellular activities, the molecular mechanisms by which proneural factors such as Mash1 regulate neurogenesis are poorly understood, with the identity of their target genes remaining largely unknown. We have performed a genome wide location analyses using ChIP-on-chip on both embryonic brain progenitors and neural stem cell cultures, in order to characterize the transcriptional program regulated by Mash1. Promoter occupancy data was combined with transcript profiling of embryonic progenitors and neural stem cell cultures overexpressing or mutant for Mash1, resulting in the identification of a large number of genes regulated by Mash1. The wide range of molecular functions and cellular processes associated with Mash1 targets shows that this proneural factor works as a master regulator of neurogenesis, directly controlling the specification of neural progenitors but also the later steps of neuronal differentiation and neurite outgrowth. Surprisingly, we have found that Mash1 also positively regulates a large number of genes that promote cellular proliferation, including activators of the cell cycle such as E2f1 and FoxM1, and downstream components of the hippo signalling pathway. Mutational analysis revealed that Mash1is indeed required for the generation of dividing progenitors in the embryonic brain and for normal divisions of neural stem cells in culture. Our studies have identified a novel function of the proneural protein Mash1, and uncovered an unexpectedly direct link between the phase of expansion of neural progenitors and the subsequent phases of cell cycle exit and neuronal differentiation.