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

Published version
Peer-reviewed

Type

Article

Change log

Authors

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

Abstract

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.

Description

Keywords

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

Journal Title

Dev Cell

Conference Name

Journal ISSN

1534-5807
1878-1551

Volume Title

58

Publisher

Elsevier BV
Sponsorship
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)