Enteroendocrine cells (EEs) represent a heterogeneous cell population in intestine and exert endocrine functions by secreting a diverse array of neuropeptides. Although many transcription factors (TFs) required for specification of EEs have been identified in both mammals and Drosophila, it is not understood how these TFs work together to generate this considerable subtype diversity. Here we show that EE diversity in adult Drosophila is generated via an “additive hierarchical TF cascade”. Specifically, a combination of a master TF, a secondary-level TF and a tertiary-level TF constitute a “TF code” for generating EE diversity. We also discover a high degree of post-specification plasticity of EEs, as changes in the code—including as few as one distinct TF—allow efficient switching of subtype identities. Our study thus reveals a hierarchically-organized TF code that underlies EE diversity and plasticity in Drosophila, which can guide investigations of EEs in mammals and inform their application in medicine.

肠内分泌细胞 (EEs) 代表肠道中的异质细胞群，并通过分泌多种神经肽发挥内分泌功能。尽管已经在哺乳动物和果蝇中鉴定了 EE 规范所需的许多转录因子 (TF) ，但尚不清楚这些 TF 如何协同工作以产生这种相当大的亚型多样性。在这里，我们展示了成年果蝇的 EE 多样性是通过“附加分层 TF 级联”生成的。具体来说，主 TF、二级 TF 和三级 TF 的组合构成了用于生成 EE 多样性的“TF 代码”。我们还发现 EE 具有高度的后规范可塑性，因为代码的变化——包括少至一个不同的 TF——允许有效地切换子类型身份。因此，我们的研究揭示了一个分层组织的 TF 代码，它是果蝇EE 多样性和可塑性的基础，它可以指导对哺乳动物 EE 的研究并为其在医学中的应用提供信息。