德国马克斯·普朗克生物智能研究所Christian Mayer课题组发现，空间增强子激活影响小鼠胚胎发育过程中抑制性神经元的特性。这一研究成果于2024年3月25日发表在国际顶尖学术期刊《自然—神经科学》上。

研究人员结合使用了体内CRISPR干扰、谱系追踪和ChIP序列分析，结果表明转录因子MEIS2在小鼠胚胎发育过程中，通过结合投射神经元特异性基因的增强子区域，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，才能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可抑制MEIS2-DLX5依赖性激活投射神经元特异性增强子。Meis2基因突变会导致调控增强子的激活减少，从而影响GABA能的分化。研究人员提出了一个差异结合模型，即转录因子在顺式调控元件上的结合决定了不同的基因表达程序，从而调控小鼠神经节隆起细胞命运的分化。

据介绍，哺乳动物端脑包含不同类型的GABA能投射神经元和中间神经元，它们起源于胚胎基底节的生发区。生发区的遗传信息如何决定细胞类型尚不清楚。

附：英文原文

Title: Spatial enhancer activation influences inhibitory neuron identity during mouse embryonic development

Author: Dvoretskova, Elena, Ho, May C., Kittke, Volker, Neuhaus, Florian, Vitali, Ilaria, Lam, Daniel D., Delgado, Irene, Feng, Chao, Torres, Miguel, Winkelmann, Juliane, Mayer, Christian

Issue&Volume: 2024-03-25

Abstract: 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.

DOI: 10.1038/s41593-024-01611-9

Source: https://www.nature.com/articles/s41593-024-01611-9