Flatworm-specific transcriptional regulators promote the specification of tegumental progenitors in Schistosoma mansoni

  1. George R Wendt
  2. Julie NR Collins
  3. Jimin Pei
  4. Mark S Pearson
  5. Hayley M Bennett
  6. Alex Loukas
  7. Matthew Berriman
  8. Nick V Grishin
  9. James J Collins  Is a corresponding author
  1. University of Texas Southwestern Medical Center, United States
  2. James Cook University, Australia
  3. Wellcome Trust Sanger Institute, United Kingdom

Abstract

Schistosomes infect more than 200 million people. These parasitic flatworms rely on a syncytial outer-coat called the tegument to survive within the vasculature of their host. Although the tegument is pivotal for their survival, little is known about maintenance of this tissue during the decades schistosomes survive in the bloodstream. Here, we demonstrate that the tegument relies on stem cells (neoblasts) to specify fusogenic progenitors that replace tegumental cells lost to turnover. Molecular characterization of neoblasts and tegumental progenitors led to the discovery of two flatworm-specific zinc finger proteins that are essential for tegumental cell specification. These proteins are homologous to a protein essential for neoblast-driven epidermal maintenance in free-living flatworms. Therefore, we speculate that related parasites (i.e., tapeworms and flukes) employ similar strategies to control tegumental maintenance. Since parasitic flatworms infect every vertebrate species, understanding neoblast-driven tegumental maintenance could identify broad-spectrum therapeutics to fight diseases caused by these parasites.

Data availability

The following data sets were generated
    1. Wellcome Trust Sanger Institute
    (2017) Characterising_Schistosoma_mansoni_stem_cell_populations
    ERS1987962, ERS1987961, ERS1987958, ERS1987958, ERS1987957, ERS1987948, ERS1987946, ERS1987945, ERS1987942.

Article and author information

Author details

  1. George R Wendt

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Julie NR Collins

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Jimin Pei

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Mark S Pearson

    Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0002-1544
  5. Hayley M Bennett

    Wellcome Trust Sanger Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  6. Alex Loukas

    Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Australia
    Competing interests
    The authors declare that no competing interests exist.
  7. Matthew Berriman

    Wellcome Trust Sanger Institute, Cambridge, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9581-0377
  8. Nick V Grishin

    Department of Biophysics, University of Texas Southwestern Medical Center, Dallas, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. James J Collins

    Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, United States
    For correspondence
    JamesJ.Collins@UTSouthwestern.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5237-1004

Funding

National Institutes of Health (R01AI121037)

  • James J Collins

Wellcome (107475/Z/15/Z)

  • Matthew Berriman
  • James J Collins

National Institutes of Health (R01GM094575)

  • Nick V Grishin

Welch Foundation (I1505)

  • Nick V Grishin

National Health and Medical Research Council

  • Alex Loukas

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

Ethics

Animal experimentation: In adherence to the Animal Welfare Act and the Public Health Service Policy on Humane Care and Use of Laboratory Animals, all experiments with and care of vertebrate animals were performed in accordance with protocols approved by the Institutional Animal Care and Use Committee (IACUC) of the UT Southwestern Medical Center (protocol approval number APN 2014-0072).

Reviewing Editor

  1. Nipam H Patel, University of California, Berkeley, United States

Publication history

  1. Received: October 30, 2017
  2. Accepted: March 19, 2018
  3. Accepted Manuscript published: March 20, 2018 (version 1)
  4. Version of Record published: April 30, 2018 (version 2)
  5. Version of Record updated: August 20, 2018 (version 3)

Copyright

© 2018, Wendt 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

  • 3,377
    Page views
  • 386
    Downloads
  • 34
    Citations

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

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. George R Wendt
  2. Julie NR Collins
  3. Jimin Pei
  4. Mark S Pearson
  5. Hayley M Bennett
  6. Alex Loukas
  7. Matthew Berriman
  8. Nick V Grishin
  9. James J Collins
(2018)
Flatworm-specific transcriptional regulators promote the specification of tegumental progenitors in Schistosoma mansoni
eLife 7:e33221.
https://doi.org/10.7554/eLife.33221

Further reading

    1. Developmental Biology
    Hidenobu Miyazawa, Marteinn T Snaebjornsson ... Alexander Aulehla
    Research Article

    How cellular metabolic state impacts cellular programs is a fundamental, unresolved question. Here we investigated how glycolytic flux impacts embryonic development, using presomitic mesoderm (PSM) patterning as the experimental model. First, we identified fructose 1,6-bisphosphate (FBP) as an in vivo sentinel metabolite that mirrors glycolytic flux within PSM cells of post-implantation mouse embryos. We found that medium-supplementation with FBP, but not with other glycolytic metabolites, such as fructose 6-phosphate and 3-phosphoglycerate, impaired mesoderm segmentation. To genetically manipulate glycolytic flux and FBP levels, we generated a mouse model enabling the conditional overexpression of dominant active, cytoplasmic PFKFB3 (cytoPFKFB3). Overexpression of cytoPFKFB3 indeed led to increased glycolytic flux/FBP levels and caused an impairment of mesoderm segmentation, paralleled by the downregulation of Wnt-signaling, reminiscent of the effects seen upon FBP-supplementation. To probe for mechanisms underlying glycolytic flux-signaling, we performed subcellular proteome analysis and revealed that cytoPFKFB3 overexpression altered subcellular localization of certain proteins, including glycolytic enzymes, in PSM cells. Specifically, we revealed that FBP supplementation caused depletion of Pfkl and Aldoa from the nuclear-soluble fraction. Combined, we propose that FBP functions as a flux-signaling metabolite connecting glycolysis and PSM patterning, potentially through modulating subcellular protein localization.

    1. Developmental Biology
    2. Genetics and Genomics
    Janani Ramachandran, Weiqiang Zhou ... Steven A Vokes
    Research Article Updated

    The larynx enables speech while regulating swallowing and respiration. Larynx function hinges on the laryngeal epithelium which originates as part of the anterior foregut and undergoes extensive remodeling to separate from the esophagus and form vocal folds that interface with the adjacent trachea. Here we find that sonic hedgehog (SHH) is essential for epithelial integrity in the mouse larynx as well as the anterior foregut. During larynx-esophageal separation, low Shh expression marks specific domains of actively remodeling epithelium that undergo an epithelial-to-mesenchymal transition (EMT) characterized by the induction of N-Cadherin and movement of cells out of the epithelial layer. Consistent with a role for SHH signaling in regulating this process, Shh mutants undergo an abnormal EMT throughout the anterior foregut and larynx, marked by a cadherin switch, movement out of the epithelial layer and cell death. Unexpectedly, Shh mutant epithelial cells are replaced by a new population of FOXA2-negative cells that likely derive from adjacent pouch tissues and form a rudimentary epithelium. These findings have important implications for interpreting the etiology of HH-dependent birth defects within the foregut. We propose that SHH signaling has a default role in maintaining epithelial identity throughout the anterior foregut and that regionalized reductions in SHH trigger epithelial remodeling.