Developing tissues interpret dynamic changes in morphogen activity to generate cell type diversity. To quantitatively study bone morphogenetic protein (BMP) signaling dynamics in the mouse neural tube, we developed an embryonic stem cell differentiation system tailored for growing tissues. Differentiating cells form striking self-organized patterns of dorsal neural tube cell types driven by sequential phases of BMP signaling that are observed both in vitro and in vivo. Data-driven biophysical modeling showed that these dynamics result from coupling fast negative feedback with slow positive regulation of signaling by the specification of an endogenous BMP source. Thus, in contrast to relays that propagate morphogen signaling in space, we identify a BMP signaling relay that operates in time. This mechanism allows for a rapid initial concentration-sensitive response that is robustly terminated, thereby regulating balanced sequential cell type generation. Our study provides an experimental and theoretical framework to understand how signaling dynamics are exploited in developing tissues.

中文翻译：

---

通过 BMP 信号转导的时间中继在发育中的小鼠神经管中形成自组织模式


发育中的组织解释形态发生活性的动态变化以产生细胞类型多样性。为了定量研究小鼠神经管中的骨形态发生蛋白 （BMP） 信号动力学，我们开发了一种为生长组织量身定制的胚胎干细胞分化系统。分化细胞形成引人注目的背神经管细胞类型的自组织模式，由在体外 和体内观察到 的 BMP 信号传导的连续阶段驱动。数据驱动的生物物理模型表明，这些动力学是通过内源性 BMP 源的规范将快速负反馈与缓慢的信号传导正调节耦合而成的。因此，与在太空中传播形态发生素信号传导的中继相反，我们确定了随时间运行的 BMP 信号传导中继。这种机制允许快速的初始浓度敏感反应，该反应被稳健终止，从而调节平衡的连续细胞类型生成。我们的研究提供了一个实验和理论框架，以了解如何在发育组织中利用信号动力学。