One of the hallmarks of the cerebral cortex is the extreme diversity of interneurons^1,2,3. The two largest subtypes of cortical interneurons, parvalbumin- and somatostatin-positive cells, are morphologically and functionally distinct in adulthood but arise from common lineages within the medial ganglionic eminence^{4,5,6,7,8,9,10,11}. This makes them an attractive model for studying the generation of cell diversity. Here we examine how developmental changes in transcription and chromatin structure enable these cells to acquire distinct identities in the mouse cortex. Generic interneuron features are first detected upon cell cycle exit through the opening of chromatin at distal elements. By constructing cell-type-specific gene regulatory networks, we observed that parvalbumin- and somatostatin-positive cells initiate distinct programs upon settling within the cortex. We used these networks to model the differential transcriptional requirement of a shared regulator, Mef2c, and confirmed the accuracy of our predictions through experimental loss-of-function experiments. We therefore reveal how a common molecular program diverges to enable these neuronal subtypes to acquire highly specialized properties by adulthood. Our methods provide a framework for examining the emergence of cellular diversity, as well as for quantifying and predicting the effect of candidate genes on cell-type-specific development.

大脑皮层的标志之一是中间神经元的极端多样性^1,2,3。皮质中间神经元的两个最大亚型，小白蛋白阳性细胞和生长抑素阳性细胞，在成年期在形态和功能上是不同的，但起源于内侧神经节隆起内的常见谱系^{4,5,6,7,8,9,10,11}. 这使它们成为研究细胞多样性产生的有吸引力的模型。在这里，我们研究了转录和染色质结构的发育变化如何使这些细胞在小鼠皮层中获得不同的身份。在细胞周期通过远端元件处染色质的开口退出时，首先检测到通用的中间神经元特征。通过构建细胞类型特异性基因调控网络，我们观察到小白蛋白和生长抑素阳性细胞在进入皮层后会启动不同的程序。我们使用这些网络来模拟共享调节器Mef2c的差异转录要求，并通过实验性的功能丧失实验证实了我们预测的准确性。因此，我们揭示了一个常见的分子程序是如何发散的，以使这些神经元亚型能够在成年期获得高度专业化的特性。我们的方法为检查细胞多样性的出现以及量化和预测候选基因对细胞类型特异性发育的影响提供了一个框架。