1. Developmental Biology
  2. Neuroscience
Download icon

Intermediate progenitors support migration of neural stem cells into dentate gyrus outer neurogenic niches

  1. Branden R Nelson  Is a corresponding author
  2. Rebecca D Hodge
  3. Ray AM Daza
  4. Prem Tripathi
  5. Sebastian J Arnold
  6. Kathleen J Millen
  7. Robert Hevner  Is a corresponding author
  1. Seattle Children's Research Institute, United States
  2. University of San Diego, United States
  3. University of Freiburg, Germany
Research Article
  • Cited 5
  • Views 1,648
  • Annotations
Cite this article as: eLife 2020;9:e53777 doi: 10.7554/eLife.53777

Abstract

The hippocampal dentate gyrus (DG) is a unique brain region maintaining neural stem cells (NCSs) and neurogenesis into adulthood. We used multiphoton imaging to visualize for genetically defined progenitor subpopulations in live slices across key stages of mouse DG development testing decades old static models of DG formation, with molecular identification, genetic-lineage tracing, and mutant analyses. We found novel progenitor migrations, timings, dynamic cell-cell interactions, signaling activities, and routes underlie mosaic DG formation. Intermediate progenitors (IPs, Tbr2+) pioneered migrations, supporting and guiding later emigrating NSCs (Sox9+) through multiple transient zones prior to converging at the nascent outer adult niche in a dynamic settling process, generating all prenatal and postnatal granule neurons in defined spatiotemporal order. IPs (Dll1+) extensively targeted contacts to mitotic NSCs (Notch active), revealing a substrate for cell-cell contact support during migrations, a developmental feature maintained in adults. Mouse DG formation shares conserved features of human neocortical expansion.

Article and author information

Author details

  1. Branden R Nelson

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    For correspondence
    branden.nelson@seattlechildrens.org
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-2941-0153
  2. Rebecca D Hodge

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Ray AM Daza

    Department of Pathology, University of San Diego, San Diego, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Prem Tripathi

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Sebastian J Arnold

    Institute of Experimental and Clinical Pharmacology and Toxicology, Signaling Research Centers BIOSS and CIBSS, Faculty of Medicine, University of Freiburg, Freiburg, Germany
    Competing interests
    The authors declare that no competing interests exist.
  6. Kathleen J Millen

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9978-675X
  7. Robert Hevner

    Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, United States
    For correspondence
    rhevner@ucsd.edu
    Competing interests
    The authors declare that no competing interests exist.

Funding

National Institutes of Health (R21 MH087070)

  • Robert Hevner

National Institutes of Health (R21 MH087070)

  • Branden R Nelson

National Institutes of Health (R01 NS085081)

  • Robert Hevner

National Institutes of Health (R01 NS092339)

  • Robert Hevner

German Research Foundation Heisenberg-Program (AR 732/3-1)

  • Sebastian J Arnold

Germany's Excellence Strategy (CIBSS - EXC-2189 - Project ID 390939984)

  • Sebastian J Arnold

National Institutes of Health (R21 OD023838)

  • Branden R Nelson

National Institutes of Health (R21 OD023838)

  • Kathleen J Millen

National Institutes of Health (R01 NS099027)

  • Kathleen J Millen

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. All of the animals were handled according to approved institutional animal care and use committee (IACUC) protocols (#13535) of the Seattle Children's Research Institute.

Reviewing Editor

  1. Francois Guillemot, The Francis Crick Institute, United Kingdom

Publication history

  1. Received: November 20, 2019
  2. Accepted: March 30, 2020
  3. Accepted Manuscript published: April 2, 2020 (version 1)
  4. Accepted Manuscript updated: April 3, 2020 (version 2)
  5. Version of Record published: April 15, 2020 (version 3)

Copyright

© 2020, Nelson 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

  • 1,648
    Page views
  • 311
    Downloads
  • 5
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

  1. Further reading

Further reading

    1. Developmental Biology
    2. Neuroscience
    Hiroki Takechi et al.
    Research Article

    Transmembrane protein Golden goal (Gogo) interacts with atypical cadherin Flamingo to direct R8 photoreceptor axons in the Drosophila visual system. However, the precise mechanisms underlying Gogo regulation during columnar- and layer-specific R8 axon targeting are unknown. Our studies demonstrated that the insulin secreted from surface and cortex glia switches the phosphorylation status of Gogo, thereby regulating its two distinct functions. Non-phosphorylated Gogo mediates the initial recognition of the glial protrusion in the center of the medulla column, whereas phosphorylated Gogo suppresses radial filopodia extension by counteracting Flamingo to maintain a one axon to one column ratio. Later, Gogo expression ceases during the midpupal stage, thus allowing R8 filopodia to extend vertically into the M3 layer. These results demonstrate that the long- and short-range signaling between the glia and R8 axon growth cones regulates growth cone dynamics in a stepwise manner, and thus shape the entire organization of the visual system.

    1. Developmental Biology
    Mamoru Ishii et al.
    Research Article

    A notable example of spiral architecture in organs is the mammalian cochlear duct, where the morphology is critical for hearing function. Genetic studies have revealed necessary signaling molecules, but it remains unclear how cellular dynamics generate elongating, bending, and coiling of the cochlear duct. Here, we show that extracellular signal-regulated kinase (ERK) activation waves control collective cell migration during the murine cochlear duct development using deep tissue live-cell imaging, Förster resonance energy transfer (FRET)-based quantitation, and mathematical modeling. Long-term FRET imaging reveals that helical ERK activation propagates from the apex duct tip concomitant with the reverse multicellular flow on the lateral side of the developing cochlear duct, resulting in advection-based duct elongation. Moreover, model simulations, together with experiments, explain that the oscillatory wave trains of ERK activity and the cell flow are generated by mechanochemical feedback. Our findings propose a regulatory mechanism to coordinate the multicellular behaviors underlying the duct elongation during development.