1. Developmental Biology
Download icon

Transient hypothyroidism favors oligodendrocyte generation providing functional remyelination in the adult mouse brain

  1. Sylvie Remaud
  2. Fernando C Ortiz
  3. Marie Perret-Jeanneret
  4. Marie-Stéphane Aigrot
  5. Jean-David Gothié
  6. Csaba Fekete
  7. Zsuzsanna Kvárta-Papp
  8. Balázs Gereben
  9. Dominique Langui
  10. Catherine Lubetzki
  11. Maria Cecilia Angulo
  12. Bernard Zalc
  13. Barbara Demeneix  Is a corresponding author
  1. Muséum d'Histoire Naturelle, Sorbonne Universités, France
  2. INSERM U1128, France
  3. Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, France
  4. Institute of Experimental Medicine, Hungarian Academy of Sciences, Hungary
Research Article
  • Cited 27
  • Views 1,828
  • Annotations
Cite this article as: eLife 2017;6:e29996 doi: 10.7554/eLife.29996

Abstract

In the adult brain, both neurons and oligodendrocytes can be generated from neural stem cells located within the Sub-Ventricular Zone (SVZ). Physiological signals regulating neuronal versus glial fate are largely unknown. Here we report that a thyroid hormone (T3)-free window, with or without a demyelinating insult, provides a favorable environment for SVZ-derived oligodendrocyte progenitor generation. After demyelination, oligodendrocytes derived from these newly-formed progenitors provide functional remyelination, restoring normal conduction speed. The cellular basis for neuronal versus glial determination in progenitors involves asymmetric partitioning of EGFR and TRα1, expression of which favor glio-and neurogenesis, respectively. Moreover, EGFR+ oligodendrocyte progenitors, but not neuroblasts, express high levels of a T3-inactivating deiodinase, Dio3. Thus, TRα absence with high levels of Dio3 provides double-pronged blockage of T3 action during glial lineage commitment. These findings not only transform our understanding of how T3 orchestrates adult brain lineage decisions, but also provide potential insight into demyelinating disorders.

Article and author information

Author details

  1. Sylvie Remaud

    CNRS UMR 7221, Muséum d'Histoire Naturelle, Sorbonne Universités, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  2. Fernando C Ortiz

    INSERM U1128, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  3. Marie Perret-Jeanneret

    CNRS UMR 7221, Muséum d'Histoire Naturelle, Sorbonne Universités, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  4. Marie-Stéphane Aigrot

    ICM-GH Pitié-Salpêtrière, Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Jean-David Gothié

    CNRS UMR 7221, Muséum d'Histoire Naturelle, Sorbonne Universités, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  6. Csaba Fekete

    Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  7. Zsuzsanna Kvárta-Papp

    Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  8. Balázs Gereben

    Department of Endocrine Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary
    Competing interests
    The authors declare that no competing interests exist.
  9. Dominique Langui

    ICM-GH Pitié-Salpêtrière, Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  10. Catherine Lubetzki

    ICM-GH Pitié-Salpêtrière, Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  11. Maria Cecilia Angulo

    INSERM U1128, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  12. Bernard Zalc

    ICM-GH Pitié-Salpêtrière, Sorbonne Universités UPMC Univ Paris 06, Inserm, CNRS, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  13. Barbara Demeneix

    CNRS UMR 7221, Muséum d'Histoire Naturelle, Sorbonne Universités, Paris, France
    For correspondence
    bdem@mnhn.fr
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4544-971X

Funding

Association Française contre les Myopathies

  • Sylvie Remaud
  • Barbara Demeneix

European Commission

  • Barbara Demeneix

Agence Nationale de la Recherche

  • Sylvie Remaud
  • Bernard Zalc
  • Barbara Demeneix

Fondation pour la Recherche Médicale

  • Maria Cecilia Angulo

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 experimental procedures involving mice in our study were approved by the French Ministry of Agriculture (authorization number, 01169.02).

Reviewing Editor

  1. Klaus-Armin Nave, Max-Planck-Institute for Experimental Medicine, Germany

Publication history

  1. Received: June 29, 2017
  2. Accepted: September 5, 2017
  3. Accepted Manuscript published: September 6, 2017 (version 1)
  4. Accepted Manuscript updated: September 7, 2017 (version 2)
  5. Version of Record published: September 20, 2017 (version 3)

Copyright

© 2017, Remaud 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

  • 1,828
    Page views
  • 415
    Downloads
  • 27
    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)

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

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

Further reading

    1. Developmental Biology
    2. Neuroscience
    Tania Moreno-Mármol et al.
    Research Article

    The vertebrate eye-primordium consists of a pseudostratified neuroepithelium, the optic vesicle (OV), in which cells acquire neural retina or retinal pigment epithelium (RPE) fates. As these fates arise, the OV assumes a cup-shape, influenced by mechanical forces generated within the neural retina. Whether the RPE passively adapts to retinal changes or actively contributes to OV morphogenesis remains unexplored. We generated a zebrafish Tg(E1-bhlhe40:GFP) line to track RPE morphogenesis and interrogate its participation in OV folding. We show that, in virtual absence of proliferation, RPE cells stretch and flatten, thereby matching the retinal curvature and promoting OV folding. Localized interference with the RPE cytoskeleton disrupts tissue stretching and OV folding. Thus, extreme RPE flattening and accelerated differentiation are efficient solutions adopted by fast-developing species to enable timely optic cup formation. This mechanism differs in amniotes, in which proliferation drives RPE expansion with a much-reduced need of cell flattening.

    1. Developmental Biology
    2. Neuroscience
    Meike E van der Heijden et al.
    Research Article

    Preterm infants that suffer cerebellar insults often develop motor disorders and cognitive difficulty. Excitatory granule cells, the most numerous neuron type in the brain, are especially vulnerable and likely instigate disease by impairing the function of their targets, the Purkinje cells. Here, we use regional genetic manipulations and in vivo electrophysiology to test whether excitatory neurons establish the firing properties of Purkinje cells during postnatal mouse development. We generated mutant mice that lack the majority of excitatory cerebellar neurons and tracked the structural and functional consequences on Purkinje cells. We reveal that Purkinje cells fail to acquire their typical morphology and connectivity, and that the concomitant transformation of Purkinje cell firing activity does not occur either. We also show that our mutant pups have impaired motor behaviors and vocal skills. These data argue that excitatory cerebellar neurons define the maturation time-window for postnatal Purkinje cell functions and refine cerebellar-dependent behaviors.