Sandberg Magnus, Flandin Pierre, Silberberg Shanni, Su-Feher Linda, Price James D, Hu Jia Sheng, Kim Carol, Visel Axel, Nord Alex S, Rubenstein John L R
Department of Psychiatry, University of California, San Francisco, San Francisco, CA 94143, USA.
Department of Psychiatry and Behavioral Sciences, University of California, Davis, Davis, CA 95817, USA; Department of Neurobiology, Physiology, and Behavior, University of California, Davis, Davis, CA 95616, USA.
Neuron. 2016 Sep 21;91(6):1260-1275. doi: 10.1016/j.neuron.2016.08.020.
The embryonic basal ganglia generates multiple projection neurons and interneuron subtypes from distinct progenitor domains. Combinatorial interactions of transcription factors and chromatin are thought to regulate gene expression. In the medial ganglionic eminence, the NKX2-1 transcription factor controls regional identity and, with LHX6, is necessary to specify pallidal projection neurons and forebrain interneurons. Here, we dissected the molecular functions of NKX2-1 by defining its chromosomal binding, regulation of gene expression, and epigenetic state. NKX2-1 binding at distal regulatory elements led to a repressed epigenetic state and transcriptional repression in the ventricular zone. Conversely, NKX2-1 is required to establish a permissive chromatin state and transcriptional activation in the sub-ventricular and mantle zones. Moreover, combinatorial binding of NKX2-1 and LHX6 promotes transcriptionally permissive chromatin and activates genes expressed in cortical migrating interneurons. Our integrated approach provides a foundation for elucidating transcriptional networks guiding the development of the MGE and its descendants.
胚胎基底神经节从不同的祖细胞区域产生多种投射神经元和中间神经元亚型。转录因子和染色质的组合相互作用被认为可调节基因表达。在内侧神经节隆起中，NKX2-1转录因子控制区域特征，并且与LHX6一起，是指定苍白球投射神经元和前脑中间神经元所必需的。在这里，我们通过定义其染色体结合、基因表达调控和表观遗传状态来剖析NKX2-1的分子功能。NKX2-1在远端调控元件处的结合导致室管膜区的表观遗传状态受到抑制和转录抑制。相反，在脑室下区和套层区，需要NKX2-1来建立允许的染色质状态和转录激活。此外，NKX2-1和LHX6的组合结合促进转录允许的染色质，并激活在皮质迁移中间神经元中表达的基因。我们的综合方法为阐明指导内侧神经节隆起及其后代发育的转录网络奠定了基础。
