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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 circuitry1,2. Continuous production of neuroblasts is controlled by the SVZ microenvironmental niche3,4. 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 brain5. Here we show in mice that SVZ-generated astrocytes express high levels of thrombospondin 4 (Thbs4)6,7, 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 Thbs4hi astrocyte production from the postnatal SVZ niche. Tamoxifen-inducible nestin-creERtm4 lineage tracing demonstrated that it is these SVZ-generated Thbs4hi 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 production8. Consequently, Thbs4 homozygous knockout mice (Thbs4KO/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 Thbs4KO/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 roles9,10.

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Figure 1: SVZ generation of Thbs4hi astrocytes.
Figure 2: Thbs4hi astrocyte production after photothrombotic cortical injury.
Figure 3: Notch signalling and regulation of injury-induced SVZ astrogenesis.
Figure 4: SVZ astrogenesis defects in Thbs4 mutant mice after cortical injury.

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Acknowledgements

We thank D. Melton (Harvard) for R26R-NICD mice; T. Honjo (Kyoto) for RBPjk-flox mice; F. Wang for R26R-tdTomato mice; E. Rawlins (Cambridge) for Foxj1-creERt2 mice; B. Deneen (B.C.M.) and S. Singh for discussions; G. Lyons, R. Andersen, P. Heine, D. Fromme and S. Collins for project assistance; Duke Flow Cytometry Facility for help with FACS; W. Li and Duke Center for In vivo microscopy/brain imaging for MRI analyses; and T. Lechler, A. West and B. Hogan for comments on manuscript. This work was supported by National Biomedical Technology Resource Center Grant P41 RR005959 (C.L.) of P41 EB015897 to Duke Center for In Vivo Microscopy; George and Jean Brumley Endowment, Sontag Foundation, David and Lucile Packard Foundation, March of Dimes, and NIH Director’s New Innovator Award 1 DP2 OD004453-01 (C.T.K.).

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Authors and Affiliations

Authors

Contributions

E.J.B. performed injury and biochemical experiments; D.L. performed gene expression and live-imaging experiments; K.A. performed in vivo immunoprecipitation experiments; P.P.-G. performed SVZ antibody staining and analyses; R.J., H.S. and D.S.W. assisted with injuries and their analyses; C.L. performed MRI scanning and quantitative analyses; C.E. provided reagents and experimental insight; C.T.K. performed transplantations and conceived the project. E.J.B., D.L. and R.J. assembled figures and C.T.K. wrote the paper. All authors discussed results and commented on the manuscript.

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Correspondence to Chay T. Kuo.

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Supplementary Figures

This file contains Supplementary Figures 1-14. (PDF 7408 kb)

Live-imaging of lineage-traced rostral migratory stream Neuroblasts

This movie shows representative live-imaging of tdTomato+ rostral migratory stream (RMS) neuroblasts in acute brain slices, from N4; R26R-tdTomato mice induced with tamoxifen at P6 and imaged 3 weeks later. Left = rostral. Bidirectional travel of RMS neuroblasts in acute slice preparations had been reported previously34. Images were captured once every 5 minutes; total time = 55 minutes. (MOV 6955 kb)

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Benner, E., Luciano, D., Jo, R. et al. Protective astrogenesis from the SVZ niche after injury is controlled by Notch modulator Thbs4. Nature 497, 369–373 (2013). https://doi.org/10.1038/nature12069

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