BACKGROUND Lineage segregation from multipotent epithelia is a central theme in development and in adult stem cell plasticity. Previously, we demonstrated that striated and smooth muscle cells share a common progenitor within their epithelium of origin, the lateral domain of the somite-derived dermomyotome. However, what controls the segregation of these muscle subtypes remains unknown. We use this in vivo bifurcation of fates as an experimental model to uncover the underlying mechanisms of lineage diversification from bipotent progenitors. RESULTS Using the strength of spatio-temporally controlled gene missexpression in avian embryos, we report that Notch harbors distinct pro-smooth muscle activities depending on the duration of the signal; short periods prevent striated muscle development and extended periods, through Snail1, promote cell emigration from the dermomyotome towards a smooth muscle fate. Furthermore, we define a Muscle Regulatory Network, consisting of Id2, Id3, FoxC2 and Snail1, which acts in concert to promote smooth muscle by antagonizing the pro-myogenic activities of Myf5 and Pax7, which induce striated muscle fate. Notch and BMP closely regulate the network and reciprocally reinforce each other¿s signal. In turn, components of the network strengthen Notch signaling, while Pax7 silences this signaling. These feedbacks augment the robustness and flexibility of the network regulating muscle subtype segregation. CONCLUSIONS Our results demarcate the details of the Muscle Regulatory Network, underlying the segregation of muscle sublineages from the lateral dermomyotome, and exhibit how factors within the network promote the smooth muscle at the expense of the striated muscle fate. This network acts as an exemplar demonstrating how lineage segregation occurs within epithelial primordia by integrating inputs from competing factors.

中文翻译：

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通过 Notch 依赖性调节网络分离横纹肌和平滑肌谱系。

背景与多能上皮细胞的谱系分离是发育和成体干细胞可塑性的中心主题。以前，我们证明横纹肌和平滑肌细胞在它们的起源上皮内共享一个共同的祖细胞，即体节衍生的 dermomyotome 的侧域。然而，控制这些肌肉亚型分离的因素仍然未知。我们使用这种体内命运分叉作为实验模型来揭示双能祖细胞谱系多样化的潜在机制。结果 利用鸟类胚胎中时空控制的基因错误表达的强度，我们报告说 Notch 具有不同的促平滑肌活动，这取决于信号的持续时间；短时间防止横纹肌发育和延长时间，通过 Snail1，促进细胞从 dermomyotome 迁移到平滑肌的命运。此外，我们定义了一个肌肉调节网络，由 Id2、Id3、FoxC2 和 Snail1 组成，它们通过拮抗诱导横纹肌命运的 Myf5 和 Pax7 的促生肌活动来协同促进平滑肌。Notch 和 BMP 密切调节网络并相互加强彼此的信号。反过来，网络的组件会加强 Notch 信号，而 Pax7 会抑制该信号。这些反馈增强了调节肌肉亚型分离的网络的稳健性和灵活性。结论我们的结果划定了肌肉调节网络的细节，这是从外侧真皮肌节分离肌肉亚系的基础，并展示网络中的因素如何以牺牲横纹肌命运为代价促进平滑肌。该网络作为一个范例，展示了如何通过整合来自竞争因素的输入，在上皮原基内发生谱系分离。