The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes
The balance of Id3 and E47 determines neural stem/precursor cell differentiation into astrocytes
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DOI：
10.15252/embj.201591118
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发表时间：
2015-11-12
期刊：
影响因子：
11.4
通讯作者：
Schachtrup, Christian
中科院分区：
文献类型：
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作者：
Bohrer, Christian;Pfurr, Sabrina;Schachtrup, Christian
脑室下区（SVZ）的成体神经干/前体细胞（NSPCs）是CNS疾病中神经元替代的内源性来源。然而，成年神经发生在脑损伤后受到损害，有利于神经胶质细胞的命运，这主要归因于NSPC环境的变化。然而，目前还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Id 3的遗传耗竭减少了创伤性脑损伤后皮质病变区SVZ衍生的成人NSPCs产生的星形胶质细胞的数量。皮质脑损伤导致SVZ干细胞龛中BMP-2和Id 3的快速上调。Id 3（-/-）成人NSPCs未能分化为BMP-2诱导的星形胶质细胞，而缺乏Id 3控制的转录因子E47的NSPCs在缺乏BMP-2的情况下容易分化为星形胶质细胞。从机制上讲，E47抑制了成年NSPCs中几个星形胶质细胞特异性基因的表达。这些结果鉴定了Id 3作为BMP-2诱导的转录调节因子，促进CNS损伤后成人NSPC分化为星形胶质细胞，并揭示了损伤后CNS中环境变化和NSPC分化之间的分子联系。
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.