Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells

  1. Isabelle Maria Blomfield
  2. Brenda Rocamonde
  3. Maria del Mar Masdeu
  4. Eskeatnaf Mulugeta
  5. Stefania Vaga
  6. Debbie LC van den Berg
  7. Emmanuelle Huillard
  8. Francois Guillemot  Is a corresponding author
  9. Noelia Urbán  Is a corresponding author
  1. The Francis Crick Institute, United Kingdom
  2. Institut du Cerveau et de la Moelle Epinière (ICM), France
  3. Erasmus MC, Netherlands

Abstract

Quiescence is essential for the long-term maintenance of adult stem cells but how stem cells maintain quiescence is poorly understood. Here we show that neural stem cells in the adult mouse hippocampus actively transcribe the pro-activation factor Ascl1 regardless of their activated or quiescent states. We found that the inhibitor of DNA binding protein Id4 is enriched in quiescent neural stem cells and that elimination of Id4 results in abnormal accumulation of Ascl1 protein and premature stem cell activation. Accordingly, Id4 and other Id proteins promote elimination of Ascl1 protein in neural stem cell cultures. Id4 sequesters Ascl1 heterodimerisation partner E47, promoting Ascl1 protein degradation and stem cell quiescence. Our results highlight the importance of non-transcriptional mechanisms for the maintenance of neural stem cell quiescence and reveal a role for Id4 as a quiescence-inducing factor, in contrast with its role of promoting the proliferation of embryonic neural progenitors.

Data availability

Sequencing data have been deposited in GEO under accession code GSE116997

The following data sets were generated

Article and author information

Author details

  1. Isabelle Maria Blomfield

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4412-0226
  2. Brenda Rocamonde

    Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France
    Competing interests
    No competing interests declared.
  3. Maria del Mar Masdeu

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    No competing interests declared.
  4. Eskeatnaf Mulugeta

    Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    No competing interests declared.
  5. Stefania Vaga

    The Francis Crick Institute, London, United Kingdom
    Competing interests
    No competing interests declared.
  6. Debbie LC van den Berg

    Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6026-8808
  7. Emmanuelle Huillard

    Institut du Cerveau et de la Moelle Epinière (ICM), Paris, France
    Competing interests
    No competing interests declared.
  8. Francois Guillemot

    The Francis Crick Institute, London, United Kingdom
    For correspondence
    Francois.Guillemot@crick.ac.uk
    Competing interests
    Francois Guillemot, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0432-5067
  9. Noelia Urbán

    The Francis Crick Institute, London, United Kingdom
    For correspondence
    noelia.urban@imba.oeaw.ac.at
    Competing interests
    No competing interests declared.

Funding

Francis Crick Institute (FC0010089)

  • Eskeatnaf Mulugeta

Medical Research Council (U117570528)

  • Francois Guillemot

Wellcome (106187/Z/14/Z)

  • Francois Guillemot

H2020 Marie Skłodowska-Curie Actions (799214)

  • Debbie LC van den Berg

Ligue Contre le Cancer (PJA 20131200481)

  • Emmanuelle Huillard

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

Reviewing Editor

  1. Gary L Westbrook, Oregon Health and Science University, United States

Ethics

Animal experimentation: All procedures involving animals and their care were performed in accordance with the guidelines of the Francis Crick Institute, national guidelines and laws. This study was approved by the Animal Ethics Committee and by the UK Home Office (PPL PB04755CC). All surgery was performed under terminal pentobarbital anaesthesia, and every effort was made to minimise suffering.

Version history

  1. Received: May 17, 2019
  2. Accepted: September 24, 2019
  3. Accepted Manuscript published: September 25, 2019 (version 1)
  4. Version of Record published: October 22, 2019 (version 2)

Copyright

© 2019, Blomfield 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

  • 4,218
    views
  • 651
    downloads
  • 61
    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. Isabelle Maria Blomfield
  2. Brenda Rocamonde
  3. Maria del Mar Masdeu
  4. Eskeatnaf Mulugeta
  5. Stefania Vaga
  6. Debbie LC van den Berg
  7. Emmanuelle Huillard
  8. Francois Guillemot
  9. Noelia Urbán
(2019)
Id4 promotes the elimination of the pro-activation factor Ascl1 to maintain quiescence of adult hippocampal stem cells
eLife 8:e48561.
https://doi.org/10.7554/eLife.48561

Share this article

https://doi.org/10.7554/eLife.48561

Further reading

    1. Neuroscience
    Tara Ghafari, Cecilia Mazzetti ... Ole Jensen
    Research Article

    Evidence suggests that subcortical structures play a role in high-level cognitive functions such as the allocation of spatial attention. While there is abundant evidence in humans for posterior alpha band oscillations being modulated by spatial attention, little is known about how subcortical regions contribute to these oscillatory modulations, particularly under varying conditions of cognitive challenge. In this study, we combined MEG and structural MRI data to investigate the role of subcortical structures in controlling the allocation of attentional resources by employing a cued spatial attention paradigm with varying levels of perceptual load. We asked whether hemispheric lateralization of volumetric measures of the thalamus and basal ganglia predicted the hemispheric modulation of alpha-band power. Lateral asymmetry of the globus pallidus, caudate nucleus, and thalamus predicted attention-related modulations of posterior alpha oscillations. When the perceptual load was applied to the target and the distractor was salient caudate nucleus asymmetry predicted alpha-band modulations. Globus pallidus was predictive of alpha-band modulations when either the target had a high load, or the distractor was salient, but not both. Finally, the asymmetry of the thalamus predicted alpha band modulation when neither component of the task was perceptually demanding. In addition to delivering new insight into the subcortical circuity controlling alpha oscillations with spatial attention, our finding might also have clinical applications. We provide a framework that could be followed for detecting how structural changes in subcortical regions that are associated with neurological disorders can be reflected in the modulation of oscillatory brain activity.

    1. Neuroscience
    Annette Pisanski, Mitchell Prostebby ... Silvia Pagliardini
    Research Article

    The lateral parafacial area (pFL) is a crucial region involved in respiratory control, particularly in generating active expiration through an expiratory oscillatory network. Active expiration involves rhythmic abdominal (ABD) muscle contractions during late-expiration, increasing ventilation during elevated respiratory demands. The precise anatomical location of the expiratory oscillator within the ventral medulla’s rostro-caudal axis is debated. While some studies point to the caudal tip of the facial nucleus (VIIc) as the oscillator’s core, others suggest more rostral areas. Our study employed bicuculline (a γ-aminobutyric acid type A [GABA-A] receptor antagonist) injections at various pFL sites (–0.2 mm to +0.8 mm from VIIc) to investigate the impact of GABAergic disinhibition on respiration. These injections consistently elicited ABD recruitment, but the response strength varied along the rostro-caudal zone. Remarkably, the most robust and enduring changes in tidal volume, minute ventilation, and combined respiratory responses occurred at more rostral pFL locations (+0.6/+0.8 mm from VIIc). Multivariate analysis of the respiratory cycle further differentiated between locations, revealing the core site for active expiration generation with this experimental approach. Our study advances our understanding of neural mechanisms governing active expiration and emphasizes the significance of investigating the rostral pFL region.