Journal
EMBO JOURNAL
Volume 34, Issue 22, Pages 2804-2819Publisher
WILEY
DOI: 10.15252/embj.201591118
Keywords
astrocyte-specific genes; basic helix-loop-helix transcription factor; bone morphogenetic protein; traumatic brain injury; vascular damage
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Funding
- International Graduate Academy Fellowship
- German Academic Exchange Service Fellowship
- Fazit Foundation Graduate Fellowship
- European Commission FP7 Grant [PIRG08-GA-2010-276989, PIRG08-GA-2010-276906]
- NEUREX
- German Research Foundation [SCHA 1442/3-2]
- German Federal Ministry of Education and Research [BMBF 01EO1303]
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Adult neural stem/precursor cells (NSPCs) of the subventricular zone (SVZ) are an endogenous source for neuronal replacement in CNS disease. However, adult neurogenesis is compromised after brain injury in favor of a glial cell fate, which is mainly attributed to changes in the NSPC environment. Yet, it is unknown how this unfavorable extracellular environment translates into a transcriptional program altering NSPC differentiation. Here, we show that genetic depletion of the transcriptional regulator Id3 decreased the number of astrocytes generated from SVZ-derived adult NSPCs in the cortical lesion area after traumatic brain injury. Cortical brain injury resulted in rapid BMP-2 and Id3 up-regulation in the SVZ stem cell niche. Id3(-/-) adult NSPCs failed to differentiate into BMP-2-induced astrocytes, while NSPCs deficient for the Id3-controlled transcription factor E47 readily differentiated into astrocytes in the absence of BMP-2. Mechanistically, E47 repressed the expression of several astrocyte-specific genes in adult NSPCs. These results identify Id3 as the BMP-2-induced transcriptional regulator, promoting adult NSPC differentiation into astrocytes upon CNS injury and reveal a molecular link between environmental changes and NSPC differentiation in the CNS after injury.
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