1. Developmental Biology
Download icon

Jagged and Delta ligands control distinct events during airway progenitor cell differentiation

  1. Maria R Stupnikov
  2. Ying Yang
  3. Munemasa Mori
  4. Jining Lu
  5. Wellington V Cardoso  Is a corresponding author
  1. Columbia University Medical Center, United States
Research Article
  • Cited 4
  • Views 1,200
  • Annotations
Cite this article as: eLife 2019;8:e50487 doi: 10.7554/eLife.50487

Abstract

Notch signaling regulates cell fate selection during development in multiple organs including the lung. Previous studies on the role of Notch in the lung focused mostly on Notch pathway core components or receptor-specific functions. It is unclear, however, how individual (Dll1/Dll4/Jag1/Jag2) or families of ligands (Delta/Jagged) influence differentiation of airway epithelial progenitors. Using mouse genetic models we show major differences in Jag and Dll in regulation and establishment of cell fate. Jag ligands had a major impact in balancing distinct cell populations in conducting airways, but had no role in establishment of domains and cellular abundance in the neuroendocrine (NE) microenvironment. Surprisingly, Dll ligands were crucial in restricting cell fate and size of NE bodies and showed an overlapping role with Jag in differentiation of NE-associated secretory (club) cells. These mechanisms may potentially play a role in human conditions that result in aberrant NE differentiation, including NE hyperplasias and cancer.

Article and author information

Author details

  1. Maria R Stupnikov

    Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5349-5233
  2. Ying Yang

    Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Munemasa Mori

    Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jining Lu

    Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Wellington V Cardoso

    Columbia Center for Human Development, Department of Medicine, Pulmonary Allergy Critical Care, Columbia University Medical Center, New York, United States
    For correspondence
    wvc2104@cumc.columbia.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8868-9716

Funding

National Heart, Lung, and Blood Institute (R35-HL135834-01)

  • Wellington V Cardoso

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocol (AAAS0503) of Columbia University.

Reviewing Editor

  1. Edward E Morrisey, University of Pennsylvania, United States

Publication history

  1. Received: July 24, 2019
  2. Accepted: October 18, 2019
  3. Accepted Manuscript published: October 21, 2019 (version 1)
  4. Version of Record published: December 2, 2019 (version 2)

Copyright

© 2019, Stupnikov et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,200
    Page views
  • 312
    Downloads
  • 4
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Download citations (links to download the citations from this article in formats compatible with various reference manager tools)

Open citations (links to open the citations from this article in various online reference manager services)

Further reading

    1. Cell Biology
    2. Developmental Biology
    Nikhil R Bhagwat et al.
    Research Article Updated

    Protein modification by SUMO helps orchestrate the elaborate events of meiosis to faithfully produce haploid gametes. To date, only a handful of meiotic SUMO targets have been identified. Here, we delineate a multidimensional SUMO-modified meiotic proteome in budding yeast, identifying 2747 conjugation sites in 775 targets, and defining their relative levels and dynamics. Modified sites cluster in disordered regions and only a minority match consensus motifs. Target identities and modification dynamics imply that SUMOylation regulates all levels of chromosome organization and each step of meiotic prophase I. Execution-point analysis confirms these inferences, revealing functions for SUMO in S-phase, the initiation of recombination, chromosome synapsis and crossing over. K15-linked SUMO chains become prominent as chromosomes synapse and recombine, consistent with roles in these processes. SUMO also modifies ubiquitin, forming hybrid oligomers with potential to modulate ubiquitin signaling. We conclude that SUMO plays diverse and unanticipated roles in regulating meiotic chromosome metabolism.

    1. Developmental Biology
    Qiuyu Guo et al.
    Research Article Updated

    The canonical Wnt pathway transcriptional co-activator β-catenin regulates self-renewal and differentiation of mammalian nephron progenitor cells (NPCs). We modulated β-catenin levels in NPC cultures using the GSK3 inhibitor CHIR99021 (CHIR) to examine opposing developmental actions of β-catenin. Low CHIR-mediated maintenance and expansion of NPCs are independent of direct engagement of TCF/LEF/β-catenin transcriptional complexes at low CHIR-dependent cell-cycle targets. In contrast, in high CHIR, TCF7/LEF1/β-catenin complexes replaced TCF7L1/TCF7L2 binding on enhancers of differentiation-promoting target genes. Chromosome confirmation studies showed pre-established promoter–enhancer connections to these target genes in NPCs. High CHIR-associated de novo looping was observed in positive transcriptional feedback regulation to the canonical Wnt pathway. Thus, β-catenin’s direct transcriptional role is restricted to the induction of NPCs, where rising β-catenin levels switch inhibitory TCF7L1/TCF7L2 complexes to activating LEF1/TCF7 complexes at primed gene targets poised for rapid initiation of a nephrogenic program.