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A cellular hierarchy of Notch and Kras signaling controls cell fate specification in the developing mouse salivary gland.

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Chatzeli, Lemonia 
Bordeu, Ignacio 
Han, Seungmin 
Bisetto, Sara 
Waheed, Zahra 


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.



Kras, Krt14, Notch, acini, branching, development, differentiation, duct, potency, salivary gland, Mice, Animals, Cell Lineage, Cell Differentiation, Signal Transduction, Stem Cells, Epithelial Cells, Salivary Glands

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Dev Cell

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Elsevier BV
Wellcome Trust (098357/Z/12/Z)
Wellcome Trust (219478/Z/19/Z)
Wellcome Trust (092096/Z/10/Z)
Cancer Research Uk (None)
Wellcome Trust (105942/Z/14/Z)
Medical Research Council (MR/P019013/1)
Engineering and Physical Sciences Research Council (EP/P034616/1)
Cancer Research UK (C54674/A27487)
Medical Research Council (MC_PC_17230)