Temporal control of cortico-thalamic neuron specification by regulation of Neurogenin activity and Polycomb repressive complexes

<jats:title>Summary</jats:title><jats:p>Neural progenitor cells (NPCs) in the embryonic mammalian neocortex generate different neuronal subtypes sequentially. A long-standing hypothesis to account for this temporal fate specification process is that NPCs change their differentiation potential over time. However, the molecular mechanisms underlying these temporal changes in NPC properties are poorly understood. Here we show that Neurogenin1 and Neurogenin2 (Neurog1/2), two proneural transcription factors expressed in NPCs throughout cortical neurogenesis, specify the identity of one of the first cortical neuron subtypes generated, layer 6 cortico-thalamic neurons (CTNs). We found that <jats:italic>Neurog1/2</jats:italic> specify the CTN fate through regulation of the cortical fate determinants <jats:italic>Fezf2</jats:italic> and <jats:italic>Foxp2</jats:italic> and that this <jats:italic>Neurog</jats:italic>-induced programme becomes inactive after the period of CTN production. Two independent mechanisms contribute to the arrest of CTN neuron generation at the end of layer 6 neurogenesis, including a reduction in the transcriptional activity of Neurog1/2 and the deposition of epigenetic repressive modifications mediated by Polycomb repressive complexes at the <jats:italic>Foxp2</jats:italic> gene. Therefore, the duration of production of a cortical neuron subtype is controlled by multiple locking mechanisms involving both transcriptional and epigenetic processes.</jats:p>