Skip to main content
Journal cover image

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

Publication ,  Journal Article
Benner, EJ; Luciano, D; Jo, R; Abdi, K; Paez-Gonzalez, P; Sheng, H; Warner, DS; Liu, C; Eroglu, C; Kuo, CT
Published in: Nature
May 16, 2013

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

May 16, 2013

Volume

497

Issue

7449

Start / End Page

369 / 373

Location

England

Related Subject Headings

  • Thrombospondins
  • Signal Transduction
  • Receptor, Notch1
  • Neuroglia
  • Neural Stem Cells
  • NFI Transcription Factors
  • Mice, Knockout
  • Mice
  • General Science & Technology
  • Endocytosis
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Benner, E. J., Luciano, D., Jo, R., Abdi, K., Paez-Gonzalez, P., Sheng, H., … Kuo, C. T. (2013). Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature, 497(7449), 369–373. https://doi.org/10.1038/nature12069
Benner, Eric J., Dominic Luciano, Rebecca Jo, Khadar Abdi, Patricia Paez-Gonzalez, Huaxin Sheng, David S. Warner, Chunlei Liu, Cagla Eroglu, and Chay T. Kuo. “Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4.Nature 497, no. 7449 (May 16, 2013): 369–73. https://doi.org/10.1038/nature12069.
Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H, et al. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature. 2013 May 16;497(7449):369–73.
Benner, Eric J., et al. “Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4.Nature, vol. 497, no. 7449, May 2013, pp. 369–73. Pubmed, doi:10.1038/nature12069.
Benner EJ, Luciano D, Jo R, Abdi K, Paez-Gonzalez P, Sheng H, Warner DS, Liu C, Eroglu C, Kuo CT. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature. 2013 May 16;497(7449):369–373.
Journal cover image

Published In

Nature

DOI

EISSN

1476-4687

Publication Date

May 16, 2013

Volume

497

Issue

7449

Start / End Page

369 / 373

Location

England

Related Subject Headings

  • Thrombospondins
  • Signal Transduction
  • Receptor, Notch1
  • Neuroglia
  • Neural Stem Cells
  • NFI Transcription Factors
  • Mice, Knockout
  • Mice
  • General Science & Technology
  • Endocytosis