Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4.
Abstract
Postnatal/adult neural stem cells (NSCs) within the rodent subventricular zone (SVZ;
also called subependymal zone) generate doublecortin (Dcx)(+) neuroblasts that migrate
and integrate into olfactory bulb circuitry. Continuous production of neuroblasts
is controlled by the SVZ microenvironmental niche. It is generally thought that enhancing
the neurogenic activities of endogenous NSCs may provide needed therapeutic options
for disease states and after brain injury. However, SVZ NSCs can also differentiate
into astrocytes. It remains unclear whether there are conditions that favour astrogenesis
over neurogenesis in the SVZ niche, and whether astrocytes produced there have different
properties compared with astrocytes produced elsewhere in the brain. Here we show
in mice that SVZ-generated astrocytes express high levels of thrombospondin 4 (Thbs4),
a secreted homopentameric glycoprotein, in contrast to cortical astrocytes, which
express low levels of Thbs4. We found that localized photothrombotic/ischaemic cortical
injury initiates a marked increase in Thbs4(hi) astrocyte production from the postnatal
SVZ niche. Tamoxifen-inducible nestin-creER(tm)4 lineage tracing demonstrated that
it is these SVZ-generated Thbs4(hi) astrocytes, and not Dcx(+) neuroblasts, that home-in
on the injured cortex. This robust post-injury astrogenic response required SVZ Notch
activation modulated by Thbs4 via direct Notch1 receptor binding and endocytosis to
activate downstream signals, including increased Nfia transcription factor expression
important for glia production. Consequently, Thbs4 homozygous knockout mice (Thbs4(KO/KO))
showed severe defects in cortical-injury-induced SVZ astrogenesis, instead producing
cells expressing Dcx migrating from SVZ to the injury sites. These alterations in
cellular responses resulted in abnormal glial scar formation after injury, and significantly
increased microvascular haemorrhage into the brain parenchyma of Thbs4(KO/KO) mice.
Taken together, these findings have important implications for post-injury applications
of endogenous and transplanted NSCs in the therapeutic setting, as well as disease
states where Thbs family members have important roles.
Type
Journal articleSubject
Cerebral VentriclesCerebral Cortex
Neuroglia
Astrocytes
Cicatrix
Animals
Mice, Knockout
Mice
Brain Injuries
Thrombospondins
Signal Transduction
Cell Movement
Endocytosis
Cell Lineage
NFI Transcription Factors
Receptor, Notch1
Neural Stem Cells
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https://hdl.handle.net/10161/23279Published Version (Please cite this version)
10.1038/nature12069Publication Info
Benner, Eric J; Luciano, Dominic; Jo, Rebecca; Abdi, Khadar; Paez-Gonzalez, Patricia;
Sheng, Huaxin; ... Kuo, Chay T (2013). Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator
Thbs4. Nature, 497(7449). pp. 369-373. 10.1038/nature12069. Retrieved from https://hdl.handle.net/10161/23279.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Eric James Benner
George W. Brumley, Jr. M.D Distinguished Assistant Professor of Developmental Biology
As a neonatologist, my research interests revolve around improving the survival and
quality of life of high-risk neonates cared for in Neonatal Intensive Care Units.
My primary interest is perinatal brain injuries impacting both full-term infants and
those born prematurely. One of the most common forms of perinatal brain injury involves
damage to white matter (myelin). My laboratory has developed models of perinatal brain
injury to investigate how the endogenous neural stem cell respond
Cagla Eroglu
Professor of Cell Biology
Chunlei Liu
Associate Professor of Radiology
Magnetic Resonance Imaging (MRI) and its translational applications * Diffusion
weighted imaging * Generalized Diffusion Tensor Imaging * Ultra-high field imaging
* Image acquisition and reconstruction * High resolution and high speed imaging *
Image-contrast mechanism
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
Huaxin Sheng
Associate Professor in Anesthesiology
We have successfully developed various rodent models of brain and spinal cord injuries
in our lab, such as focal cerebral ischemia, global cerebral ischemia, head trauma,
subarachnoid hemorrhage, intracerebral hemorrhage, spinal cord ischemia and compression
injury. We also established cardiac arrest and hemorrhagic shock models for studying
multiple organ dysfunction. Our current studies focus on two projects. One is to
examine the efficacy of catalytic antioxidant in treating cerebral is
David Samuel Warner
Distinguished Distinguished Professor of Anesthesiology, in the School of Medicine
Humans may sustain a variety of forms of acute central nervous system injury including
ischemia, trauma, vasospasm, and perinatal hypoxemia. The Multidisciplinary Neuroprotection
Laboratories is dedicated to examining the pathophysiology of acute brain and spinal
cord injury with particular reference to disease states managed in the perioperative
or neurointensive care environments. Rodent recovery models of cerebral ischemia,
traumatic brain injury, cardiopulmonary bypass, subarachnoid he
This author no longer has a Scholars@Duke profile, so the information shown here reflects
their Duke status at the time this item was deposited.
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