Diversification of heart progenitor cells by EGF signaling and differential modulation of ETS protein activity

  1. Benjamin Schwarz
  2. Dominik Hollfelder
  3. Katharina Scharf
  4. Leonie Hartmann
  5. Ingolf Reim  Is a corresponding author
  1. Friedrich-Alexander University of Erlangen-Nürnberg, Germany

Abstract

For coordinated circulation, vertebrate and invertebrate hearts require stereotyped arrangements of diverse cell populations. This study explores the process of cardiac cell diversification in the Drosophila heart, focusing on the two major cardioblast subpopulations: generic working myocardial cells and inflow valve-forming ostial cardioblasts. By screening a large collection of randomly induced mutants we identified several genes involved in cardiac patterning. Further analysis revealed an unexpected, specific requirement of EGF signaling for the specification of generic cardioblasts and a subset of pericardial cells. We demonstrate that the Tbx20 ortholog Midline acts as a direct target of the EGFR effector Pointed to repress ostial fates. Furthermore, we identified Edl/Mae, an antagonist of the ETS factor Pointed, as a novel cardiac regulator crucial for ostial cardioblast specification. Combining these findings we propose a regulatory model in which the balance between activation of Pointed and its inhibition by Edl controls cardioblast subtype-specific gene expression.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files. Source data files have been provided for Figures 1, 3, 5 and 5-S1.

Article and author information

Author details

  1. Benjamin Schwarz

    Department of Biology, Division of Developmental Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  2. Dominik Hollfelder

    Department of Biology, Division of Developmental Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  3. Katharina Scharf

    Department of Biology, Division of Developmental Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  4. Leonie Hartmann

    Department of Biology, Division of Developmental Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
    Competing interests
    The authors declare that no competing interests exist.
  5. Ingolf Reim

    Department of Biology, Division of Developmental Biology, Friedrich-Alexander University of Erlangen-Nürnberg, Erlangen, Germany
    For correspondence
    ingolf.reim@fau.de
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8069-5532

Funding

Deutsche Forschungsgemeinschaft (RE 2985/1-1)

  • Ingolf Reim

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

Reviewing Editor

  1. Utpal Banerjee, University of California, Los Angeles, United States

Publication history

  1. Received: October 16, 2017
  2. Accepted: June 4, 2018
  3. Accepted Manuscript published: June 5, 2018 (version 1)
  4. Version of Record published: July 5, 2018 (version 2)

Copyright

© 2018, Schwarz 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

  • 1,177
    Page views
  • 171
    Downloads
  • 5
    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)

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. Benjamin Schwarz
  2. Dominik Hollfelder
  3. Katharina Scharf
  4. Leonie Hartmann
  5. Ingolf Reim
(2018)
Diversification of heart progenitor cells by EGF signaling and differential modulation of ETS protein activity
eLife 7:e32847.
https://doi.org/10.7554/eLife.32847

Further reading

    1. Developmental Biology
    2. Neuroscience
    Ashtyn T Wiltbank et al.
    Research Article

    Efficient neurotransmission is essential for organism survival and is enhanced by myelination. However, the genes that regulate myelin and myelinating glial cell development have not been fully characterized. Data from our lab and others demonstrates that cd59, which encodes for a small GPI-anchored glycoprotein, is highly expressed in developing zebrafish, rodent, and human oligodendrocytes (OLs) and Schwann cells (SCs), and that patients with CD59 dysfunction develop neurological dysfunction during early childhood. Yet, the function of Cd59 in the developing nervous system is currently undefined. In this study, we demonstrate that cd59 is expressed in a subset of developing SCs. Using cd59 mutant zebrafish, we show that developing SCs proliferate excessively and nerves may have reduced myelin volume, altered myelin ultrastructure, and perturbed node of Ranvier assembly. Finally, we demonstrate that complement activity is elevated in cd59 mutants and that inhibiting inflammation restores SC proliferation, myelin volume, and nodes of Ranvier to wildtype levels. Together, this work identifies Cd59 and developmental inflammation as key players in myelinating glial cell development, highlighting the collaboration between glia and the innate immune system to ensure normal neural development.

    1. Chromosomes and Gene Expression
    2. Developmental Biology
    Lewis Macdonald et al.
    Tools and Resources

    Auxin-inducible degrons are a chemical genetic tool for targeted protein degradation and are widely used to study protein function in cultured mammalian cells. Here we develop CRISPR-engineered mouse lines that enable rapid and highly specific degradation of tagged endogenous proteins in vivo. Most but not all cell types are competent for degradation. By combining ligand titrations with genetic crosses to generate animals with different allelic combinations, we show that degradation kinetics depend upon the dose of the tagged protein, ligand, and the E3 ligase substrate receptor TIR1. Rapid degradation of condensin I and condensin II - two essential regulators of mitotic chromosome structure - revealed that both complexes are individually required for cell division in precursor lymphocytes, but not in their differentiated peripheral lymphocyte derivatives. This generalisable approach provides unprecedented temporal control over the dose of endogenous proteins in mouse models, with implications for studying essential biological pathways and modelling drug activity in mammalian tissues.