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
Institute of Anatomy and Cell Biology, University of Freiburg, Freiburg, Germany Faculty of Biology, University of Freiburg, Freiburg, Germany.
Faculty of Biology, University of Freiburg, Freiburg, Germany Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, University of Freiburg, Freiburg, Germany.
EMBO J. 2015 Nov 12;34(22):2804-19. doi: 10.15252/embj.201591118. Epub 2015 Oct 5.
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.
脑室下区（SVZ）的成年神经干细胞/前体细胞（NSPCs）是中枢神经系统疾病中神经元替代的内源性来源。然而，脑损伤后成年神经发生受到损害，有利于神经胶质细胞命运，这主要归因于NSPC环境的变化。然而，尚不清楚这种不利的细胞外环境如何转化为改变NSPC分化的转录程序。在这里，我们表明转录调节因子Id3的基因缺失减少了创伤性脑损伤后皮质损伤区域中源自SVZ的成年NSPCs产生的星形胶质细胞数量。皮质脑损伤导致SVZ干细胞生态位中BMP-2和Id3迅速上调。Id3（-/-）成年NSPCs未能分化为BMP-2诱导的星形胶质细胞，而缺乏Id3控制的转录因子E47的NSPCs在没有BMP-2的情况下很容易分化为星形胶质细胞。从机制上讲，E47抑制了成年NSPCs中几种星形胶质细胞特异性基因的表达。这些结果确定Id3为BMP-2诱导的转录调节因子，促进中枢神经系统损伤后成年NSPCs分化为星形胶质细胞，并揭示了损伤后中枢神经系统环境变化与NSPC分化之间的分子联系。
