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 Prakash Tripathi
  5. Sebastian J Arnold
  6. Kathleen J Millen
  7. Robert F 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

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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

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 Prakash 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 F 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 F Hevner

National Institutes of Health (R21 MH087070)

  • Branden R Nelson

National Institutes of Health (R01 NS085081)

  • Robert F Hevner

National Institutes of Health (R01 NS092339)

  • Robert F 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.

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  1. Branden R Nelson
  2. Rebecca D Hodge
  3. Ray AM Daza
  4. Prem Prakash Tripathi
  5. Sebastian J Arnold
  6. Kathleen J Millen
  7. Robert F Hevner
(2020)
Intermediate progenitors support migration of neural stem cells into dentate gyrus outer neurogenic niches
eLife 9:e53777.
https://doi.org/10.7554/eLife.53777

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