According to the current view, cortical arealization is presaged by encoded positional information (“protomap”) through graded expression of sets of TFs along the anteroposterior and mediolateral axis in the two germinative zones of the neocortex. Neurons with distinct morphology, connectivity, neurotransmitter usage and function are tangentially organized in numerous functional domains, implicating that mechanisms of layer and area formation are interrelated. The expression of TFs in postmitotic CP neurons may regulate through feedback signalling mechanism the progenitor progeny in the germinative zone or the fate of the postmitotic neurons. Furthermore, while Fezf2 and Otx1 expression in apical VZ progenitors controls the fate specification of the LL neurons, the expression of Svet1, Cux1 and Cux2 during later stages of neurogenesis in SVZ progenitors seems to specify UL neuronal fate. For instance, suppression of the expression of Foxg1 at E10.5 is required to make a switch from generation of reelin-positive Cajal-Retzius cells, located in the marginal zone (MZ) of the cortex, to the production of neuronal subsets located in cortical plate (CP). Increasing recent evidence support the view that the precise temporal programs for production of LL and UL neuronal fates relies on intrinsic mechanisms in early and late progenitors, respectively, characterized by specific combinatorial expression of TFs at distinct developmental time points. Thus, while the early born L6 and L5 neurons extend outside the brain thalamocortical (TCA) and corticospinal motor neuron (CSMN) projections, the late-born UL neurons make interhemispheric (callosal) projections inside the brain. The birthdate of cortical neurons is directly also related to their projection identity. During mouse development, the layer specific neuronal subtypes are generated throughout embryonic (E) stages E10.5 – E17.5 in partially overlapping time windows with a peak for generation at E11.5 for L1, E12.5 (L6), E13.5 (L5), E14.5 (L4) and E16.5-E17.5 (元-L2). Neurons with different fates are produced according to an “inside-first outside-last” schedule: first, lower layer (LL) neurons (L6/L5), followed by generation of the upper layer (UL) neurons (L4/元/L2). Generation of neuronal sets with a layer-specific identity depends on an intrinsically encoded genetic program and environmental cues acting during the S-phase of the mitotic cycle. During development, the majority of cortical glutamatergic neurons are generated by radial glial cells (RGCs) in the germinative ventricular (VZ) and subventricular (SVZ) zone of the dorsolateral pallium. The mammalian neocortex (Ncx), in which neurons are arranged radially in six layers and tangentially in numerous functional domains, is a recent acquisition in brain evolution. Our findings reveal Zbtb20 as a novel temporal regulator for the generation of layer-specific neuronal identities. In addition to its effects exerted in cortical progenitors, the postmitotic expression of Zbtb20 in 元/L2 neurons starting at birth may contribute to their proper differentiation and migration. Zbtb20 implements these temporal effects in part by binding to promoter of the orphan nuclear receptor CoupTF1/Nr2f1. This defect was due to a temporal misbalance in the production of earlier versus later born neurons, leading to a progressive diminishing of the progenitor pool for the generation of 元-L2 neurons. Zbtb20 knock out mice exhibited enhanced populations of early born L6-L4 neuronal subtypes and a dramatic reduction of the late born 元/L2 neurons. Here, we report that during embyogenesis transcription factor Zbtb20 has a dynamic spatio-temporal expression pattern in mitotic cortical progenitors through which it modulates the sequential generation of cortical neuronal layer identities. Transcription factor Zbtb20 has been shown to play a role for hippocampal development but whether it is implicated in mammalian neocortical morphogenesis remains unknown. During corticogenesis, genetic programs encoded in progenitor cells at different developmental stages and inherited in postmitotic neurons specify distinct layer and area identities.
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