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

Benner, Eric J

Luciano, Dominic

Jo, Rebecca

Abdi, Khadar

Paez-Gonzalez, Patricia

Sheng, Huaxin

Warner, David S

Liu, Chunlei

Eroglu, Cagla

Kuo, Chay T

2021-06-01T14:09:19Z

2021-06-01T14:09:19Z

2013-05

2021-06-01T14:09:17Z

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.

nature12069

0028-0836

1476-4687

https://hdl.handle.net/10161/23279

eng

Springer Science and Business Media LLC

Nature

10.1038/nature12069

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

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

Journal article

Sheng, Huaxin|0000-0002-4325-2940

Eroglu, Cagla|0000-0002-7204-0218

369

373

7449

School of Medicine

Pediatrics, Neonatology

Duke

Pediatrics

Clinical Science Departments

Anesthesiology

Neurobiology

Duke Institute for Brain Sciences

Surgery

Anesthesiology, Neuroanesthesia

Basic Science Departments

University Institutes and Centers

Institutes and Provost's Academic Units

Faculty

Cell Biology

Duke Science & Society

Initiatives

Published

497