The protomap is propagated to cortical plate neurons through an Eomes-dependent intermediate map

The cortical area map is initially patterned by transcription factor (TF) gradients in the neocortical primordium, which define a protomap in the embryonic ventricular zone (VZ). However, mechanisms that propagate regional identity from VZ progenitors to cortical plate (CP) neurons are unknown. Here we show that the VZ, subventricular zone (SVZ), and CP contain distinct molecular maps of regional identity, reflecting different gene expression gradients in radial glia progenitors, intermediate progenitors, and projection neurons, respectively. The intermediate map in SVZ is modulated by Eomes (also known as Tbr2), a T-box TF. Eomes inactivation caused rostrocaudal shifts in SVZ and CP gene expression, with loss of corticospinal axons and gain of corticotectal projections. These findings suggest that cortical areas and connections are shaped by sequential maps of regional identity, propagated by the Pax6 -> Eomes -> Tbr1 TF cascade. In humans, PAX6, EOMES, and TBR1 have been linked to intellectual disability and autism. To determine the role of Eomes in the propagation of the protomap to cortical plate neurons, used microarray analysis of E14.5 cortex from five wild type and three Eomes knockout mice.大脑皮层区域图谱最初由新皮质原基内的转录因子（transcription factor, TF）梯度所塑造，该梯度在胚胎脑室区（ventricular zone, VZ）中定义了原图谱。然而，将区域身份从VZ祖细胞传递至皮质板（cortical plate, CP）神经元的机制仍未明确。本研究发现，VZ、室下区（subventricular zone, SVZ）以及CP分别包含独特的区域身份分子图谱，分别对应放射状胶质细胞祖细胞、中间祖细胞与投射神经元中不同的基因表达梯度。SVZ中的中间图谱受到Eomes（亦称为Tbr2）这一T-box转录因子的调控。Eomes功能失活会导致SVZ与CP的基因表达出现颅尾轴方向偏移，伴随皮质脊髓轴突的丢失以及皮质顶盖投射的增多。上述研究结果提示，大脑皮层区域及其神经连接由依次传递的区域身份图谱所塑造，该传递过程由Pax6→Eomes→Tbr1转录因子级联反应介导。在人类中，PAX6、EOMES与TBR1已被证实与智力障碍及自闭症相关。为明确Eomes在原图谱向皮质板神经元传递过程中的作用，本研究对5只野生型小鼠与3只Eomes敲除小鼠的胚胎第14.5天（E14.5）皮层样本开展了基因芯片分析（microarray analysis）。