The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes. (5th October 2015)

• Record Type: Journal Article
• Authors: Bohrer, Christian; Pfurr, Sabrina; Mammadzada, Könül; Schildge, Sebastian; Plappert, Leandra; Hils, Miriam; Pous, Lauriane; Rauch, Katharina S; Dumit, Verónica I; Pfeifer, Dietmar; Dengjel, Jörn; Kirsch, Matthias; Schachtrup, Kristina; Schachtrup, Christian
• Is Part Of: EMBO journal. Volume 34:Number 22(2015)
• Page Start: 2804
• Page End: 2819
• Publication Date: 2015-10-05
• Subjects: astrocyte‐specific genes -- basic helix–loop–helix transcription factor -- bone morphogenetic protein -- traumatic brain injury -- vascular damage; Molecular biology -- Periodicals; 572.805
• DOI: 10.15252/embj.201591118
• Languages: English
• ISSNs: 0261-4189

Abstract

Abstract: 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. Synopsis: Our study shows that cortical brain injury causes temporary environmental changes within the subventricular zone (SVZ) stem cell niche, resulting in an altered balance of the transcriptional regulators Id3 and E47 in neural stem/precursor cells (NSPCs), leading to preferential differentiation of NSPCs into astrocytes. Traumatic brain injury results in increased BMP‐2 abundance in the SVZ. Elevated BMP‐2 levels are translated into a rapid increase in Id3 expression in adult NSPC subpopulations, specifically in Olig2 + C cells and Thbs4 + SVZ‐born astrocytes. Id3 then heterodimerizes with the bHLH transcription factor E47 and releases E47‐mediated repression of astrocyte‐specific gene expression. Consequently, adult NSPCs preferentially differentiate into astrocytes and contribute to the cortical lesion astrocyte population. Abstract : Transcription factor interplay triggered by brain injury compromises adult neurogenesis through derepression of astrocyte‐specific gene expression.