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Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4.

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Date
2013-05
Authors
Benner, Eric J
Luciano, Dominic
Jo, Rebecca
Abdi, Khadar
Paez-Gonzalez, Patricia
Sheng, Huaxin
Warner, David S
Liu, Chunlei
Eroglu, Cagla
Kuo, Chay T
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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 article
Subject
Cerebral Ventricles
Cerebral 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
Permalink
https://hdl.handle.net/10161/23279
Published Version (Please cite this version)
10.1038/nature12069
Publication 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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Scholars@Duke

Benner

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
Eroglu

Cagla Eroglu

Associate 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.
Sheng

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
Warner

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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