Regenerative neurogenic response from glia requires insulin driven neuron-glia communication

  1. Neale J Harrison
  2. Elizabeth Connolly
  3. Alicia Gascón Gubieda
  4. Zidan Yang
  5. Benjamin Altenhein
  6. Maria Losada Perez
  7. Marta Moreira
  8. Jun Sun
  9. Alicia Hidalgo  Is a corresponding author
  1. University of Birmingham, United Kingdom
  2. University of Cologne, Germany
  3. Instituto Cajal, Consejo Superior de Investigaciones Cientificas (CSIC), Spain

Abstract

Understanding how injury to the Central Nervous System (CNS) induces de novo neurogenesis in animals would help promote regeneration in humans. Regenerative neurogenesis could originate from glia and glial Neuron-Glia antigen-2 (NG2) may sense injury-induced neuronal signals, but these are unknown. Here, we used Drosophila to search for genes functionally related the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Alterations in Ia-2 function induced neural stem cell gene expression, injury increased ia-2 expression and induced ectopic neural stem cells. Using genetic analysis and lineage tracing, we demonstrate that Ia-2 and Kon regulate Drosophila insulin-like peptide 6 (Dilp-6), to induce glial proliferation and neural stem cells from glia. Ectopic neural stem cells can divide, and limited de novo neurogenesis could be traced back to glial cells. Altogether, Ia-2 and Dilp-6 drive a neuron-glia relay that restores glia, and reprograms glia into neural stem cells for regeneration.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

The following previously published data sets were used

Article and author information

Author details

  1. Neale J Harrison

    School of Biosciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6821-4089
  2. Elizabeth Connolly

    School of Biosciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  3. Alicia Gascón Gubieda

    School of Biosciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  4. Zidan Yang

    School of Biosciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  5. Benjamin Altenhein

    Biocenter, University of Cologne, Cologne, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Maria Losada Perez

    Instituto Cajal, Consejo Superior de Investigaciones Cientificas (CSIC), Madrid, Spain
    Competing interests
    The authors declare that no competing interests exist.
  7. Marta Moreira

    School of Biosciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  8. Jun Sun

    School of Biosciences, University of Birmingham, Birmingham, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  9. Alicia Hidalgo

    School of Biosciences, University of Birmingham, Birmingham, United Kingdom
    For correspondence
    a.hidalgo@bham.ac.uk
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8041-5764

Funding

Biotechnology and Biological Sciences Research Council (BB/L008343/1)

  • Neale J Harrison
  • Marta Moreira
  • Alicia Hidalgo

Biotechnology and Biological Sciences Research Council (BB/R00871X/1)

  • Marta Moreira
  • Alicia Hidalgo

Biotechnology and Biological Sciences Research Council (MIBTP Studentship)

  • Elizabeth Connolly

Marie Curie International Incoming Post-Doctoral Fellowship (TOLKEDA)

  • Jun Sun
  • Alicia Hidalgo

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

Copyright

© 2021, Harrison 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

  • 3,034
    views
  • 401
    downloads
  • 15
    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. Neale J Harrison
  2. Elizabeth Connolly
  3. Alicia Gascón Gubieda
  4. Zidan Yang
  5. Benjamin Altenhein
  6. Maria Losada Perez
  7. Marta Moreira
  8. Jun Sun
  9. Alicia Hidalgo
(2021)
Regenerative neurogenic response from glia requires insulin driven neuron-glia communication
eLife 10:e58756.
https://doi.org/10.7554/eLife.58756

Share this article

https://doi.org/10.7554/eLife.58756

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.