Wellcome Trust, Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Centre, University of Cambridge, Cambridge CB2 0AW, UK.
Wellcome Trust, Cancer Research UK Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK; Department of Applied Mathematics and Theoretical Physics, Centre for Mathematical Sciences, University of Cambridge, Cambridge CB3 0WA, UK; Departamento de Física, Facultad de Ciencias Físicas y Matemáticas, Universidad de Chile, 837.0415 Santiago, Chile.
Dev Cell. 2023 Jan 23;58(2):94-109.e6. doi: 10.1016/j.devcel.2022.12.009.
The development of the mouse salivary gland involves a tip-driven process of branching morphogenesis that takes place in concert with differentiation into acinar, myoepithelial, and ductal (basal and luminal) sub-lineages. By combining clonal lineage tracing with a three-dimensional (3D) reconstruction of the branched epithelial network and single-cell RNA-seq analysis, we show that in tips, a heterogeneous population of renewing progenitors transition from a Krt14+ multipotent state to unipotent states via two transcriptionally distinct bipotent states, one restricted to the Krt14+ basal and myoepithelial lineage and the other to the Krt8+ acinar and luminal lineage. Using genetic perturbations, we show how the differential expression of Notch signaling correlates with spatial segregation, exits from multipotency, and promotes the Krt8+ lineage, whereas Kras activation promotes proacinar fate. These findings provide a mechanistic basis for how positional cues within growing tips regulate the process of lineage segregation and ductal patterning.
小鼠唾液腺的发育涉及一个尖端驱动的分支形态发生过程，该过程与腺泡、肌上皮和导管（基底和腔）亚谱系的分化同时发生。通过将克隆谱系追踪与分支上皮网络的三维（3D）重建和单细胞 RNA-seq 分析相结合，我们表明在尖端，一个异质性的更新祖细胞群体通过两个转录上不同的双潜能状态从 Krt14+多能状态过渡到单潜能状态，一个局限于 Krt14+基底和肌上皮谱系，另一个局限于 Krt8+腺泡和腔谱系。通过遗传干扰，我们展示了 Notch 信号的差异表达如何与空间分离、多能性丧失以及促进 Krt8+谱系相关，而 Kras 激活则促进前腺泡命运。这些发现为生长尖端内的位置线索如何调节谱系分离和导管模式形成过程提供了机制基础。
