Intermediate progenitors support migration of neural stem cells into dentate gyrus outer neurogenic niches
- Seattle Children's Research Institute, United States
- University of San Diego, United States
- 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.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
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Author details
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.
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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Intermediate progenitors support migration of neural stem cells into dentate gyrus outer neurogenic niches
eLife 9:e53777.
https://doi.org/10.7554/eLife.53777
Further reading
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Notch signaling has been identified as a key regulatory pathway in patterning the endocardium through activation of endothelial-to-mesenchymal transition (EMT) in the atrioventricular canal (AVC) and proximal outflow tract (OFT) region. However, the precise mechanism underlying Notch activation remains elusive. By transiently blocking the heartbeat of E9.5 mouse embryos, we found that Notch activation in the arterial endothelium was dependent on its ligand Dll4, whereas the reduced expression of Dll4 in the endocardium led to a ligand-depleted field, enabling Notch to be specifically activated in AVC and OFT by regional increased shear stress. The strong shear stress altered the membrane lipid microdomain structure of endocardial cells, which activated mTORC2 and PKC and promoted Notch1 cleavage even in the absence of strong ligand stimulation. These findings highlight the role of mechanical forces as a primary cue for endocardial patterning and provide insights into the mechanisms underlying congenital heart diseases of endocardial origin.
