MyT1 Counteracts the Neural Progenitor Program to Promote Vertebrate Neurogenesis

The generation of neurons from neural stem cells requires large-scale changes in gene expression that are controlled to a large extent by proneural transcription factors, such as Ascl1. While recent studies have characterized the differentiation genes activated by proneural factors, less is known on the mechanisms that suppress progenitor cell identity. Here, we show that Ascl1 induces the transcription factor MyT1 while promoting neuronal differentiation. We combined functional studies of MyT1 during neurogenesis with the characterization of its transcriptional program. MyT1 binding is associated with repression of gene transcription in neural progenitor cells. It promotes neuronal differentiation by counteracting the inhibitory activity of Notch signaling at multiple levels, targeting the Notch1 receptor and many of its downstream targets. These include regulators of the neural progenitor program, such as Hes1, Sox2, Id3, and Olig1. Thus, Ascl1 suppresses Notch signaling cell-autonomously via MyT1, coupling neuronal differentiation with repression of the progenitor fate. [Display omitted] •MyT1 promotes neurogenesis downstream Ascl1•MyT1 represses Notch1 receptor and many of its downstream target genes•MyT1 represses Hes1 expression by direct DNA binding and competition with RBPJ•Ascl1 suppresses Notch signaling cell-autonomously while promoting differentiation Vasconcelos et al. find that the transcription factor MyT1 promotes neuronal differentiation downstream the proneural factor Ascl1. MyT1 represses the transcription of Notch signaling components and targets genes, including important regulators of the neural progenitor program. Thus, Ascl1 activates differentiation genes while repressing the progenitor program via MyT1.