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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE

Publication: Basingstoke : Nature Publishing Group
Original Publication: London, Macmillan Journals ltd.

Astrocytes/*cytology ; Astrocytes/*metabolism ; Brain Injuries/*metabolism ; Brain Injuries/*pathology ; Cerebral Ventricles/*cytology ; Receptor, Notch1/*metabolism ; Thrombospondins/*metabolism; Animals ; Cell Lineage ; Cell Movement ; Cerebral Cortex/cytology ; Cerebral Cortex/metabolism ; Cerebral Cortex/pathology ; Cicatrix/metabolism ; Cicatrix/pathology ; Doublecortin Protein ; Endocytosis ; Mice ; Mice, Knockout ; NFI Transcription Factors/metabolism ; Neural Stem Cells/cytology ; Neuroglia/cytology ; Neuroglia/metabolism ; Neuroglia/pathology ; Signal Transduction ; Thrombospondins/deficiency ; Thrombospondins/genetics

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.

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R01 MH096979 United States MH NIMH NIH HHS; DP2 OD004453 United States OD NIH HHS; P41 EB015897 United States EB NIBIB NIH HHS; DP2 OD004453-01 United States OD NIH HHS; K12 HD043494 United States HD NICHD NIH HHS; R01 DA031833 United States DA NIDA NIH HHS; R01 NS078192 United States NS NINDS NIH HHS; P41 RR005959 United States RR NCRR NIH HHS; T32 GM008441 United States GM NIGMS NIH HHS

0 (Dcx protein, mouse)
0 (Doublecortin Protein)
0 (NFI Transcription Factors)
0 (Nfia protein, mouse)
0 (Notch1 protein, mouse)
0 (Receptor, Notch1)
0 (Thrombospondins)
0 (thrombospondin 4)

Date Created: 20130426 Date Completed: 20130604 Latest Revision: 20220309

20231215

PMC3667629

10.1038/nature12069

23615612