Single-cell analysis of the ventricular-subventricular zone reveals signatures of dorsal & ventral adult neurogenesis

  1. Arantxa Cebrian Silla
  2. Marcos Assis Assis Nascimento
  3. Stephanie A Redmond
  4. Benjamin Mansky
  5. David Wu
  6. Kirsten Obernier
  7. Ricardo Romero Rodriguez
  8. Susana Gonzalez Granero
  9. Jose Manuel García-Verdugo
  10. Daniel Lim
  11. Arturo Álvarez-Buylla  Is a corresponding author
  1. University of California, San Francisco, United States
  2. Instituto Cavanilles, Universidad de Valencia, y Unidad Mixta de Esclerosis Múltiple y Neurorregeneración, CIBERNED, Spain

Abstract

The ventricular-subventricular zone (V-SVZ), on the walls of the lateral ventricles, harbors the layrgest neurogenic niche in the adult mouse brain. Previous work has shown that neural steym/progenitor cells (NSPCs) in different locations within the V-SVZ produce different subtypes of new neurons for the olfactory bulb. The molecular signatures that underlie this regional heterogeneity remain largely unknown. Here we present a single-cell RNA-sequencing dataset of the adult mouse V-SVZ revealing two populations of NSPCs that reside in largely non-overlapping domains in either the dorsal or ventral V-SVZ. These regional differences in gene expression were further validated using a single-nucleus RNA-sequencing reference dataset of regionally microdissected domains of the V-SVZ and by immunocytochemistry and RNAscope localization. We also identify two subpopulations of young neurons that have gene expression profiles consistent with a dorsal or ventral origin. Interestingly, a subset of genes are dynamically expressed, but maintained, in the ventral or dorsal lineages. The study provides novel markers and territories to understand the region-specific regulation of adult neurogenesis.

Data availability

The RNA sequencing datasets generated for this manuscript are deposited in the following locations: scRNA-Seq and sNucRNA-Seq GEO Data Series: GSE165555.Processed data (CellRanger output .mtx and .tsv files, and Seurat Object .rds files) are available as supplementary files within the scRNA-Seq (GSE165554) or sNucRNA-Seq (GSE165551) data series or individual sample entries listed within each data series.Web-based, interactive versions of the scRNA-Seq and sNucRNA-Seq datasets are available from the University of California Santa Cruz Cell Browser: https://svzneurogeniclineage.cells.ucsc.eduThe code used to analyze the datasets and generate the figures are available at the following location: https://github.com/AlvarezBuyllaLab?tab=repositories

The following data sets were generated

Article and author information

Author details

  1. Arantxa Cebrian Silla

    Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  2. Marcos Assis Assis Nascimento

    Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  3. Stephanie A Redmond

    Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  4. Benjamin Mansky

    Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-8652-0928
  5. David Wu

    Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  6. Kirsten Obernier

    Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4025-1299
  7. Ricardo Romero Rodriguez

    Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  8. Susana Gonzalez Granero

    Instituto Cavanilles, Universidad de Valencia, y Unidad Mixta de Esclerosis Múltiple y Neurorregeneración, CIBERNED, Valencia, Spain
    Competing interests
    No competing interests declared.
  9. Jose Manuel García-Verdugo

    Instituto Cavanilles, Universidad de Valencia, y Unidad Mixta de Esclerosis Múltiple y Neurorregeneración, CIBERNED, Valencia, Spain
    Competing interests
    No competing interests declared.
  10. Daniel Lim

    Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
    Competing interests
    No competing interests declared.
  11. Arturo Álvarez-Buylla

    Department of Neurological Surgery, University of California, San Francisco, San Francisco, United States
    For correspondence
    abuylla@stemcell.ucsf.edu
    Competing interests
    Arturo Álvarez-Buylla, Cofounder and on the Scientific Advisory Board of Neurona Therapeutics..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4426-8925

Funding

Generalitat Valenciana (APOSTD2018/A113)

  • Arantxa Cebrian Silla

University of California, San Francisco (John G. Bowes Research Fund and the UCSF PBBR partially funded by the Sandler Foundation)

  • Arturo Álvarez-Buylla

National Institutes of Health (R01 NS112357)

  • Arturo Álvarez-Buylla

National Institutes of Health (F32 (NS103221))

  • Stephanie A Redmond

National Institutes of Health (K99 (NS121273))

  • Stephanie A Redmond

National Institutes of Health (F31 NS106868)

  • David Wu

National Institutes of Health (R37 HD032116)

  • Arturo Álvarez-Buylla

National Institutes of Health (R01 NS028478)

  • Arturo Álvarez-Buylla

National Institutes of Health (R01 NS113910)

  • Arturo Álvarez-Buylla

National Institutes of Health (R01 NS091544)

  • Daniel Lim

U.S. Department of Veterans Affairs (1I01 BX000252)

  • Daniel Lim

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

Reviewing Editor

  1. Joseph G Gleeson, Howard Hughes Medical Institute, The Rockefeller University, United States

Ethics

Animal experimentation: Mice were housed on a 12h day-night cycle with free access to water and food in a specific pathogen-free facility in social cages (up to 5 mice/cage) and treated according to the guidelines from the UCSF. Institutional Animal Care and Use Committee (IACUC) and NIH. All mice used in this study were healthy and immuno-competent, and did not undergo previous procedures unrelated to the experiment. CD1-elite mice (Charles River Laboratories) and hGFAP::GFP (FVB/N-Tg(GFAPGFP)14Mes/J, The Jackson Laboratory (003257)) (Zhuo et al., 1997) lines were used. Sample sizes were chosen to generate sufficient numbers of high-quality single cells for RNA sequencing, including variables such as sex, and identifying potential batch effects. Biological and technical replicates for each experiment are described in the relevant subsections below.

Version history

  1. Preprint posted: February 10, 2021 (view preprint)
  2. Received: February 17, 2021
  3. Accepted: July 13, 2021
  4. Accepted Manuscript published: July 14, 2021 (version 1)
  5. Accepted Manuscript updated: July 19, 2021 (version 2)
  6. Version of Record published: September 15, 2021 (version 3)

Copyright

© 2021, Cebrian Silla 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

  • 6,846
    Page views
  • 986
    Downloads
  • 47
    Citations

Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, 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)

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. Arantxa Cebrian Silla
  2. Marcos Assis Assis Nascimento
  3. Stephanie A Redmond
  4. Benjamin Mansky
  5. David Wu
  6. Kirsten Obernier
  7. Ricardo Romero Rodriguez
  8. Susana Gonzalez Granero
  9. Jose Manuel García-Verdugo
  10. Daniel Lim
  11. Arturo Álvarez-Buylla
(2021)
Single-cell analysis of the ventricular-subventricular zone reveals signatures of dorsal & ventral adult neurogenesis
eLife 10:e67436.
https://doi.org/10.7554/eLife.67436

Share this article

https://doi.org/10.7554/eLife.67436

Further reading

    1. Neuroscience
    Kiwamu Kudo, Kamalini G Ranasinghe ... Srikantan S Nagarajan
    Research Article

    Alzheimer’s disease (AD) is characterized by the accumulation of amyloid-β and misfolded tau proteins causing synaptic dysfunction, and progressive neurodegeneration and cognitive decline. Altered neural oscillations have been consistently demonstrated in AD. However, the trajectories of abnormal neural oscillations in AD progression and their relationship to neurodegeneration and cognitive decline are unknown. Here, we deployed robust event-based sequencing models (EBMs) to investigate the trajectories of long-range and local neural synchrony across AD stages, estimated from resting-state magnetoencephalography. The increases in neural synchrony in the delta-theta band and the decreases in the alpha and beta bands showed progressive changes throughout the stages of the EBM. Decreases in alpha and beta band synchrony preceded both neurodegeneration and cognitive decline, indicating that frequency-specific neuronal synchrony abnormalities are early manifestations of AD pathophysiology. The long-range synchrony effects were greater than the local synchrony, indicating a greater sensitivity of connectivity metrics involving multiple regions of the brain. These results demonstrate the evolution of functional neuronal deficits along the sequence of AD progression.

    1. Medicine
    2. Neuroscience
    Luisa Fassi, Shachar Hochman ... Roi Cohen Kadosh
    Research Article

    In recent years, there has been debate about the effectiveness of treatments from different fields, such as neurostimulation, neurofeedback, brain training, and pharmacotherapy. This debate has been fuelled by contradictory and nuanced experimental findings. Notably, the effectiveness of a given treatment is commonly evaluated by comparing the effect of the active treatment versus the placebo on human health and/or behaviour. However, this approach neglects the individual’s subjective experience of the type of treatment she or he received in establishing treatment efficacy. Here, we show that individual differences in subjective treatment - the thought of receiving the active or placebo condition during an experiment - can explain variability in outcomes better than the actual treatment. We analysed four independent datasets (N = 387 participants), including clinical patients and healthy adults from different age groups who were exposed to different neurostimulation treatments (transcranial magnetic stimulation: Studies 1 and 2; transcranial direct current stimulation: Studies 3 and 4). Our findings show that the inclusion of subjective treatment can provide a better model fit either alone or in interaction with objective treatment (defined as the condition to which participants are assigned in the experiment). These results demonstrate the significant contribution of subjective experience in explaining the variability of clinical, cognitive, and behavioural outcomes. We advocate for existing and future studies in clinical and non-clinical research to start accounting for participants’ subjective beliefs and their interplay with objective treatment when assessing the efficacy of treatments. This approach will be crucial in providing a more accurate estimation of the treatment effect and its source, allowing the development of effective and reproducible interventions.