The mammalian telencephalon contains distinct GABAergic projection neuron and interneuron types, originating in the germinal zone of the embryonic basal ganglia. How genetic information in the germinal zone determines cell types is unclear. Here we use a combination of in vivo CRISPR perturbation, lineage tracing and ChIP–sequencing analyses and show that the transcription factor MEIS2 favors the development of projection neurons by binding enhancer regions in projection-neuron-specific genes during mouse embryonic development. MEIS2 requires the presence of the homeodomain transcription factor DLX5 to direct its functional activity toward the appropriate binding sites. In interneuron precursors, the transcription factor LHX6 represses the MEIS2–DLX5-dependent activation of projection-neuron-specific enhancers. Mutations of Meis2 result in decreased activation of regulatory enhancers, affecting GABAergic differentiation. We propose a differential binding model where the binding of transcription factors at cis-regulatory elements determines differential gene expression programs regulating cell fate specification in the mouse ganglionic eminence.

哺乳动物端脑包含独特的 GABA 能投射神经元和中间神经元类型，起源于胚胎基底神经节的生发区。生发区的遗传信息如何决定细胞类型尚不清楚。在这里，我们结合体内 CRISPR 扰动、谱系追踪和 ChIP 测序分析，发现转录因子 MEIS2 通过在小鼠胚胎发育过程中结合投射神经元特异性基因中的增强子区域，有利于投射神经元的发育。 MEIS2 需要同源结构域转录因子 DLX5 的存在，以将其功能活性导向适当的结合位点。在中间神经元前体中，转录因子 LHX6 抑制 MEIS2-DLX5 依赖性投射神经元特异性增强子的激活。Meis2突变导致调节增强子的激活减少，影响 GABA 能分化。我们提出了一种差异结合模型，其中转录因子在顺式调节元件上的结合决定了调节小鼠神经节隆起中细胞命运规范的差异基因表达程序。