Nephron progenitor commitment is a stochastic process influenced by cell migration

  1. Kynan T Lawlor
  2. Luke Zappia
  3. James Lefevre
  4. Joo-Seop Park
  5. Nicholas A Hamilton
  6. Alicia Oshlack
  7. Melissa H Little  Is a corresponding author
  8. Alexander Nicholas Combes  Is a corresponding author
  1. Murdoch Children's Research Institute, Australia
  2. University of Queensland, Australia
  3. Cincinnati Children's Hospital Medical Center, United States
  4. Murdoch Childrens Research Institute, Australia
  5. University of Melbourne, Australia

Abstract

Progenitor self-renewal and differentiation is often regulated by spatially restricted cues within a tissue microenvironment. Here we examine how progenitor cell migration impacts regionally induced commitment within the nephrogenic niche in mice. We identify a subset of cells that express Wnt4, an early marker of nephron commitment, but migrate back into the progenitor population where they accumulate over time. Single cell RNA-seq and computational modelling of returning cells reveals that nephron progenitors can traverse the transcriptional hierarchy between self-renewal and commitment in either direction. This plasticity may enable robust regulation of nephrogenesis as niches remodel and grow during organogenesis.

Data availability

Single cell sequencing data has been deposited in GEO under accession code GSE118486. Gene lists from the single cell analysis and code for the simulation of cell migration and stochastic commitment have been provided as Supplementary Files.

The following data sets were generated

Article and author information

Author details

  1. Kynan T Lawlor

    Cell Biology, Murdoch Children's Research Institute, Parkville, Australia
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4080-5439
  2. Luke Zappia

    Cell Biology, Murdoch Children's Research Institute, Parkville, Australia
    Competing interests
    No competing interests declared.
  3. James Lefevre

    Division of Genomics of Development and Disease, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
    Competing interests
    No competing interests declared.
  4. Joo-Seop Park

    Division of Pediatric Urology and Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, United States
    Competing interests
    No competing interests declared.
  5. Nicholas A Hamilton

    Division of Genomics of Development and Disease, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia
    Competing interests
    No competing interests declared.
  6. Alicia Oshlack

    Cell Biology, Murdoch Children's Research Institute, Parkville, Australia
    Competing interests
    No competing interests declared.
  7. Melissa H Little

    Kidney Development, Disease and Regeneration, Murdoch Childrens Research Institute, Parkville, Australia
    For correspondence
    Melissa.Little@mcri.edu.au
    Competing interests
    Melissa H Little, Has consulted for and received research funding from Organovo Inc.
  8. Alexander Nicholas Combes

    Anatomy and Neuroscience, University of Melbourne, Melbourne, Australia
    For correspondence
    alexander.combes@unimelb.edu.au
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6008-8786

Funding

National Health and Medical Research Council (GNT1156567)

  • Alexander Nicholas Combes

Australian Research Council (DE150100652)

  • Alexander Nicholas Combes

Murdoch Children's Research Institute

  • Alexander Nicholas Combes

National Health and Medical Research Council (GNT1136085)

  • Melissa H Little

National Health and Medical Research Council (GNT1063989)

  • Melissa H Little

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

Ethics

Animal experimentation: All animal experiments were assessed and approved by the Murdoch Children's Research Institute Animal Ethics Committee (A783/A894) and were conducted in accordance with applicable Australian laws governing the care and use of animals for scientific purposes.

Copyright

© 2019, Lawlor 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

  • 3,603
    views
  • 434
    downloads
  • 53
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

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)

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

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

  1. Kynan T Lawlor
  2. Luke Zappia
  3. James Lefevre
  4. Joo-Seop Park
  5. Nicholas A Hamilton
  6. Alicia Oshlack
  7. Melissa H Little
  8. Alexander Nicholas Combes
(2019)
Nephron progenitor commitment is a stochastic process influenced by cell migration
eLife 8:e41156.
https://doi.org/10.7554/eLife.41156

Share this article

https://doi.org/10.7554/eLife.41156

Further reading

    1. Cancer Biology
    2. Developmental Biology
    Sara Jaber, Eliana Eldawra ... Franck Toledo
    Research Article

    Missense ‘hotspot’ mutations localized in six p53 codons account for 20% of TP53 mutations in human cancers. Hotspot p53 mutants have lost the tumor suppressive functions of the wildtype protein, but whether and how they may gain additional functions promoting tumorigenesis remain controversial. Here, we generated Trp53Y217C, a mouse model of the human hotspot mutant TP53Y220C. DNA damage responses were lost in Trp53Y217C/Y217C (Trp53YC/YC) cells, and Trp53YC/YC fibroblasts exhibited increased chromosome instability compared to Trp53-/- cells. Furthermore, Trp53YC/YC male mice died earlier than Trp53-/- males, with more aggressive thymic lymphomas. This correlated with an increased expression of inflammation-related genes in Trp53YC/YC thymic cells compared to Trp53-/- cells. Surprisingly, we recovered only one Trp53YC/YC female for 22 Trp53YC/YC males at weaning, a skewed distribution explained by a high frequency of Trp53YC/YC female embryos with exencephaly and the death of most Trp53YC/YC female neonates. Strikingly, however, when we treated pregnant females with the anti-inflammatory drug supformin (LCC-12), we observed a fivefold increase in the proportion of viable Trp53YC/YC weaned females in their progeny. Together, these data suggest that the p53Y217C mutation not only abrogates wildtype p53 functions but also promotes inflammation, with oncogenic effects in males and teratogenic effects in females.

    1. Developmental Biology
    Mengjie Li, Aiguo Tian, Jin Jiang
    Research Advance

    Stem cell self-renewal often relies on asymmetric fate determination governed by niche signals and/or cell-intrinsic factors but how these regulatory mechanisms cooperate to promote asymmetric fate decision remains poorly understood. In adult Drosophila midgut, asymmetric Notch (N) signaling inhibits intestinal stem cell (ISC) self-renewal by promoting ISC differentiation into enteroblast (EB). We have previously shown that epithelium-derived Bone Morphogenetic Protein (BMP) promotes ISC self-renewal by antagonizing N pathway activity (Tian and Jiang, 2014). Here, we show that loss of BMP signaling results in ectopic N pathway activity even when the N ligand Delta (Dl) is depleted, and that the N inhibitor Numb acts in parallel with BMP signaling to ensure a robust ISC self-renewal program. Although Numb is asymmetrically segregated in about 80% of dividing ISCs, its activity is largely dispensable for ISC fate determination under normal homeostasis. However, Numb becomes crucial for ISC self-renewal when BMP signaling is compromised. Whereas neither Mad RNA interference nor its hypomorphic mutation led to ISC loss, inactivation of Numb in these backgrounds resulted in stem cell loss due to precocious ISC-to-EB differentiation. Furthermore, we find that numb mutations resulted in stem cell loss during midgut regeneration in response to epithelial damage that causes fluctuation in BMP pathway activity, suggesting that the asymmetrical segregation of Numb into the future ISC may provide a fail-save mechanism for ISC self-renewal by offsetting BMP pathway fluctuation, which is important for ISC maintenance in regenerative guts.