Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice
- Case Western Reserve University, United States
- Augusta University, United States
- Harvard Medical School, United States
Abstract
Adult neurogenesis in the hippocampus may represent a form of plasticity in brain functions including mood, learning and memory. However, mechanisms underlying neural stem/progenitor cells (NSPCs) proliferation are not well understood. We found that Agrin, a factor critical for neuromuscular junction formation, is elevated in the hippocampus of mice that are stimulated by enriched environment (EE). Genetic deletion of the Agrn gene in excitatory neurons decreases NSPCs proliferation and increases depressing-like behavior. Low-density lipoprotein receptor-related protein 4 (Lrp4), a receptor for Agrin, is expressed in hippocampal NSPCs and its mutation blocked basal as well as EE-induced NSPCs proliferation and maturation of newborn neurons. Finally, we show that Lrp4 interacts with and activates receptor tyrosine kinase-like orphan receptor 2 (Ror2); and Ror2 mutation impairs NSPCs proliferation. Together, these observations identify a role of Agrin-Lrp4-Ror2 signaling for adult neurogenesis, uncovering previously unexpected functions of Agrin and Lrp4 in the brain.
Data availability
All data generated or analysed during this study are included in the manuscript and supporting files.
Article and author information
Author details
Funding
National Institutes of Health (MH083317)
- Lin Mei
National Institutes of Health (MH109280)
- Lin Mei
National Institutes of Health (NS082007)
- Lin Mei
National Institutes of Health (NS090083)
- Lin Mei
National Institutes of Health (AG051510)
- Lin Mei
National Institutes of Health (AG051773)
- Wen-Cheng Xiong
National Institutes of Health (AG045781)
- Wen-Cheng Xiong
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Kang Shen, Howard Hughes Medical Institute, Stanford University, United States
Ethics
Animal experimentation: All procedures involving animals were in accordance with the National Institutes of Health Guide for the care and use of Laboratory Animals and approved by Institutional Animal Care and Use Committees of Augusta University (Protocol #: 2011-0393) and Case Western Reserve University (Protocol #: 2017-0115).
Version history
- Received: January 18, 2019
- Accepted: July 2, 2019
- Accepted Manuscript published: July 3, 2019 (version 1)
- Version of Record published: July 23, 2019 (version 2)
Copyright
© 2019, Zhang 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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Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice
eLife 8:e45303.
https://doi.org/10.7554/eLife.45303
Further reading
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Probing memory of a complex visual image within a few hundred milliseconds after its disappearance reveals significantly greater fidelity of recall than if the probe is delayed by as little as a second. Classically interpreted, the former taps into a detailed but rapidly decaying visual sensory or ‘iconic’ memory (IM), while the latter relies on capacity-limited but comparatively stable visual working memory (VWM). While iconic decay and VWM capacity have been extensively studied independently, currently no single framework quantitatively accounts for the dynamics of memory fidelity over these time scales. Here, we extend a stationary neural population model of VWM with a temporal dimension, incorporating rapid sensory-driven accumulation of activity encoding each visual feature in memory, and a slower accumulation of internal error that causes memorized features to randomly drift over time. Instead of facilitating read-out from an independent sensory store, an early cue benefits recall by lifting the effective limit on VWM signal strength imposed when multiple items compete for representation, allowing memory for the cued item to be supplemented with information from the decaying sensory trace. Empirical measurements of human recall dynamics validate these predictions while excluding alternative model architectures. A key conclusion is that differences in capacity classically thought to distinguish IM and VWM are in fact contingent upon a single resource-limited WM store.
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Our ability to recall details from a remembered image depends on a single mechanism that is engaged from the very moment the image disappears from view.
