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Abstract: FR-OR046

Molecular Programs of the Progenitor Population Directing Branching Morphogenesis and Differentiation of the Collecting Duct Network

Session Information

Category: Development, Stem Cells, and Regenerative Medicine

  • 501 Development, Stem Cells, and Regenerative Medicine: Basic

Author

  • Rutledge, Elisabeth, University of Southern California, Los Angeles, California, United States

Group or Team Name

  • Andrew McMahon Lab
Background

Branching morphogenesis underpins the formation of arborized epithelial networks in many organs including the lung airways and the mammalian kidney collecting duct. Epithelial branch tip cells respond to inductive signals from the adjacent mesenchyme that regulate this process and maintain an uncommitted progenitor identity. Progenitors exit the tip to populate stalk regions where they differentiate into the regionally distinct, organ appropriate, cell types of the epithelial network.

Methods

We employed population-based and single cell RNA-sequencing (scRNA seq) screens to identify tip progenitor cell types and their differentiated progeny in the developing mouse and human kidney and validated key genes by in situ hybridization and immunostaining. Several tip-specific genes are being explored through knockout mouse studies to identify their role in tip-niche regulation. To establish lineages from ureteric progenitors to adult collecting duct cell types, we are combining cell fate studies with scRNA seq, facilitated by novel genetic tools.

Results

RNA sequencing has identified a tip-enriched gene set that include all known tip genes and conservation of tip progenitor profiles between the developing mouse and human kidney. Further, conservation is observed in other branching organ systems. Expression studies show that ureteric tips have a complex gene expression pattern and cell fate analysis demonstrates that subsets of cells have lineage restrictions in the establishment of mature cell types. We analyzed the role of Adamts18, which encodes a secreted protease in mouse tip cells within the collecting duct and lung. Adamts18 null mutants display enlarged kidneys with double ureters while all mutants exhibit reduced growth of the airways.

Conclusion

Conserved gene regulatory programs organize the kidney tip progenitor niche in mouse and human, and progenitor niches in other branching organs. Lineage-tracing and scRNA seq show mosaicism of progenitor populations and how this determines their potential to form the mature collecting duct cell types. Analyses of Adamts18 mutants give new insights into mechanisms of branching growth in several branching networks.

Funding

  • NIDDK Support