Sp9 regulates medial ganglionic eminence-derived cortical interneuron development

In the mammalian cortex, about 60% of GABAergic interneurons, mainly including parvalbumin-expressing (PV+) and somatostatin (SST+) interneurons are generated from the medial ganglionic eminence (MGE) in the subpallium and tangentially migrate to the cortex. Here we analyze the role of the Sp9 transcription factor in regulating the development of MGE-derived cortical interneurons. We show that SP9 is widely expressed in the MGE subventricular zone (SVZ) and in MGE-derived migrating interneurons. By analyzing Sp9 null and conditional mutant mice, we demonstrate that Sp9 promotes MGE progenitor proliferation in the SVZ and is required for the normal patterning of tangential migration and the laminar distribution of MGE-derived cortical GABAergic interneurons. Loss of Sp9 function results in a ~50% reduction of MGE-derived cortical interneurons, an ectopic aggregation of MGE-derived neurons in the embryonic ventral telencephalon, and an increased ratio of SST+/PV+ cortical interneurons. Finally, we provide evidence that Sp9 regulates MGE derived cortical interneuron development through promoting expression of the Lhx6 and Lhx8 transcription factors. Medial ganglionic eminence mRNA profiles of embryonic 12.5 wild type (WT) and sp9 null mutant mice were generated by deep sequencing, in triplicate, using using an illumina high-seq 2500在哺乳动物大脑皮层中，约60%的γ-氨基丁酸能中间神经元（GABAergic interneurons）主要包括小白蛋白阳性（PV+）和生长抑素阳性（SST+）中间神经元，它们均起源于腹侧端脑的内侧神经节隆起（MGE），并通过切线迁移方式抵达大脑皮层。本研究聚焦转录因子（transcription factor）Sp9在调控MGE起源的皮层中间神经元发育过程中的作用。我们发现，Sp9广泛表达于MGE的室下区（SVZ）以及MGE来源的迁移性中间神经元中。通过分析Sp9纯合敲除及条件性突变小鼠，本研究证实：Sp9可促进SVZ内MGE祖细胞的增殖，同时对MGE来源的皮层中间神经元的切线迁移模式形成及层状分布的正常建立具有必需性。Sp9功能缺失会导致MGE来源的皮层中间神经元数量减少约50%，引发MGE来源神经元在胚胎腹侧端脑内出现异位聚集，并且升高SST+/PV+皮层中间神经元的比例。最后，本研究提供证据表明，Sp9通过促进转录因子Lhx6与Lhx8的表达，来调控MGE起源的皮层中间神经元的发育。本研究采用Illumina HiSeq 2500测序平台，对胚胎12.5天的野生型（wild type, WT）及Sp9纯合敲除小鼠的MGE组织完成了三次生物学重复的深度测序，获取了其mRNA表达谱数据。