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

Neale Harrison; Elizabeth Connolly; Alicia Gascón Gubieda; Zidan Yang; Benjamin Altenhein; Maria Losada-Perez; Marta Moreira; Jun Sun; Alicia Hidalgo

doi:10.7554/eLife.58756

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

Neale Harrison, Elizabeth Connolly, Alicia Gascón Gubieda, Zidan Yang, Benjamin Altenhein, Maria Losada-Perez, Marta Moreira, Jun Sun, Alicia Hidalgo

Biosciences

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Abstract

Understanding how injury to the central nervous system 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 to the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Both loss and over-expression of ia-2 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 reprogrammes glia into neural stem cells for regeneration.

Original language	English
Article number	e58756
Number of pages	32
Journal	eLife
Volume	10
Early online date	2 Feb 2021
DOIs	https://doi.org/10.7554/eLife.58756
Publication status	Published - 12 Feb 2021

Bibliographical note

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

MSCA (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.

Acknowledgements

We thank our labs and C Rezaval for discussions and comments on the manuscript; S Corneliussen, T Schunke, and S Dietz for technical help; Y Fan, A Gould, Y Jan, J Skeath, F Schnorrer, and H Wang for reagents; A Di Maio and Birmingham Advanced Light Microscopy for assistance; Bloomington Drosophila Stock Centre for fruit-flies and Developmental Studies Hybridoma Bank, Iowa for antibodies.

© 2021, Harrison et al.

Keywords

Drosophila
Glia
regeneration
neural stem cell
insulin
IA-2
CNS injury

Access to Document

10.7554/eLife.58756Licence: Creative Commons: Attribution (CC BY)

HarrisonN2021RegenerativeFinal published version, 14.9 MBLicence: Creative Commons: Attribution (CC BY)

Tolls and neurotrophins in central nervous system regeneration and repair in Drosophila
Hidalgo, A.
Biotechnology & Biological Sciences Research Council
1/05/18 → 30/04/21
Project: Research Councils
The genetic mechanisms underlying the regenerative potential of ensheathing glial cells in Drosophila
Hidalgo, A.
Biotechnology & Biological Sciences Research Council
1/05/14 → 31/10/17
Project: Research Councils

Cite this

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title = "Regenerative neurogenic response from glia requires insulin driven neuron-glia communication",

abstract = "Understanding how injury to the central nervous system 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 to the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Both loss and over-expression of ia-2 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 reprogrammes glia into neural stem cells for regeneration.",

keywords = "Drosophila, Glia, regeneration, neural stem cell, insulin, IA-2, CNS injury",

author = "Neale Harrison and Elizabeth Connolly and Gubieda, {Alicia Gasc{\'o}n} and Zidan Yang and Benjamin Altenhein and Maria Losada-Perez and Marta Moreira and Jun Sun and Alicia Hidalgo",

note = "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 MSCA (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. Acknowledgements We thank our labs and C Rezaval for discussions and comments on the manuscript; S Corneliussen, T Schunke, and S Dietz for technical help; Y Fan, A Gould, Y Jan, J Skeath, F Schnorrer, and H Wang for reagents; A Di Maio and Birmingham Advanced Light Microscopy for assistance; Bloomington Drosophila Stock Centre for fruit-flies and Developmental Studies Hybridoma Bank, Iowa for antibodies. {\textcopyright} 2021, Harrison et al.",

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AU - Harrison, Neale

AU - Connolly, Elizabeth

AU - Gubieda, Alicia Gascón

AU - Yang, Zidan

AU - Altenhein, Benjamin

AU - Losada-Perez, Maria

AU - Moreira, Marta

AU - Sun, Jun

AU - Hidalgo, Alicia

N1 - 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 MSCA (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. Acknowledgements We thank our labs and C Rezaval for discussions and comments on the manuscript; S Corneliussen, T Schunke, and S Dietz for technical help; Y Fan, A Gould, Y Jan, J Skeath, F Schnorrer, and H Wang for reagents; A Di Maio and Birmingham Advanced Light Microscopy for assistance; Bloomington Drosophila Stock Centre for fruit-flies and Developmental Studies Hybridoma Bank, Iowa for antibodies. © 2021, Harrison et al.

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N2 - Understanding how injury to the central nervous system 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 to the NG2 homologue kon-tiki (kon), and identified Islet Antigen-2 (Ia-2), required in neurons for insulin secretion. Both loss and over-expression of ia-2 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 reprogrammes glia into neural stem cells for regeneration.

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KW - Drosophila

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KW - regeneration

KW - neural stem cell

KW - insulin

KW - IA-2

KW - CNS injury

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JO - eLife

JF - eLife

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ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

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Projects

Tolls and neurotrophins in central nervous system regeneration and repair in Drosophila

The genetic mechanisms underlying the regenerative potential of ensheathing glial cells in Drosophila

Cite this