Diogo Pinto da Cruz Sampaio e Castro - Instituto Gulbenkian de Ciência
Title: The transcription factor MyT1 counteracts the neural progenitor program to promote vertebrate neurogenesis
Abstract:
In the developing vertebrate embryo, generation of neurons at the correct time and location requires a fine balance between gene expression programs that regulate differentiation and maintenance of neural stem cells. This is to large extent regulated by the opposing forces of the Proneural and Notch pathways. While recent studies have focused on characterizing the differentiation genes activated by proneural factors such as Ascl1, less is known on the mechanisms that suppress progenitor cell identity. Here, we show that Ascl1 induces the transcription factor MyT1 at the onset of neuronal differentiation. We investigate the function of MyT1 at this critical stage by combining acute functional experiments in the mouse telencephalon, with the characterization of its transcriptional program. We found that MyT1 binding occurs mostly at active regulatory regions in undifferentiated neural stem/progenitor cells and is associated with transcriptional repression genome-wide. We further show that MyT1 acts at multiple levels to antagonize the inhibitory activity of Notch signaling, targeting both Notch pathway components and downstream targets. Notably, MyT1 promotes the downregulation of Hes1, a determinant step for the onset of neurogenesis, by competing with Rbpj for binding to the Hes1 promoter. Our results reveal a function of Ascl1 in inhibiting Notch signaling cell-autonomously, showing how activation of neuronal differentiation is tightly coordinated with repression of the progenitor program.
Title: The transcription factor MyT1 counteracts the neural progenitor program to promote vertebrate neurogenesis
Abstract:
In the developing vertebrate embryo, generation of neurons at the correct time and location requires a fine balance between gene expression programs that regulate differentiation and maintenance of neural stem cells. This is to large extent regulated by the opposing forces of the Proneural and Notch pathways. While recent studies have focused on characterizing the differentiation genes activated by proneural factors such as Ascl1, less is known on the mechanisms that suppress progenitor cell identity. Here, we show that Ascl1 induces the transcription factor MyT1 at the onset of neuronal differentiation. We investigate the function of MyT1 at this critical stage by combining acute functional experiments in the mouse telencephalon, with the characterization of its transcriptional program. We found that MyT1 binding occurs mostly at active regulatory regions in undifferentiated neural stem/progenitor cells and is associated with transcriptional repression genome-wide. We further show that MyT1 acts at multiple levels to antagonize the inhibitory activity of Notch signaling, targeting both Notch pathway components and downstream targets. Notably, MyT1 promotes the downregulation of Hes1, a determinant step for the onset of neurogenesis, by competing with Rbpj for binding to the Hes1 promoter. Our results reveal a function of Ascl1 in inhibiting Notch signaling cell-autonomously, showing how activation of neuronal differentiation is tightly coordinated with repression of the progenitor program.