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

Dev Cell. 2023 Jan 23;58(2):94-109.e6. doi: 10.1016/j.devcel.2022.12.009.

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.

Keywords: Kras; Krt14; Notch; acini; branching; development; differentiation; duct; potency; salivary gland.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Differentiation / physiology
  • Cell Lineage
  • Epithelial Cells / metabolism
  • Mice
  • Salivary Glands
  • Signal Transduction*
  • Stem Cells*