Although the role of transcription factors in fate specification of cortical interneurons is well established, how these interact with extracellular signals to regulate interneuron development is poorly understood. Here we show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. Specific losses were observed among distinct subtypes of somatostatin+/Reelin+ double-positive cells, including Hpse+ layer IV cells targeting parvalbumin+ interneurons, leading to quantitative alterations in the inhibitory circuitry of this layer. Activin-mediated ALK4 signaling in MGE cells induced interaction of Smad2 with SATB1, a transcription factor critical for somatostatin interneuron development, and promoted SATB1 nuclear translocation and repositioning within the somatostatin gene promoter. These results indicate that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.

中文翻译：

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ALK4 协调细胞外和内在信号来调节皮质生长抑素中间神经元的发育

尽管转录因子在皮质中间神经元命运规范中的作用已得到充分证实，但人们对它们如何与细胞外信号相互作用以调节中间神经元发育却知之甚少。在这里，我们证明激活素受体 ALK4 是生长抑素中间神经元规范的关键调节因子。内侧神经节隆起 (MGE) 的 GABA 能神经元中缺乏 ALK4 的小鼠在出生后皮质发育早期阶段的生长抑素中间神经元的不同亚群中表现出明显的缺陷。在生长抑素+/Reelin+双阳性细胞的不同亚型中观察到特定的损失，包括靶向小白蛋白+中间神经元的Hpse+ IV层细胞，导致该层抑制回路的定量改变。MGE 细胞中激活素介导的 ALK4 信号传导诱导 Smad2 与 SATB1（对生长抑素中间神经元发育至关重要的转录因子）相互作用，并促进 SATB1 在生长抑素基因启动子内的核易位和重新定位。这些结果表明内在转录程序与 MGE 细胞环境中存在的细胞外信号相互作用，以调节皮质中间神经元规范。