Department of Pharmacology, University of Heidelberg, Germany.
Mol Cell Neurosci. 2011 Jan;46(1):325-32. doi: 10.1016/j.mcn.2010.10.004. Epub 2010 Oct 30.
The cytokine TWEAK is expressed in the brain and is induced in cerebral ischemia and other brain disorders. TWEAK regulates proliferation and differentiation of progenitor cells but its effect on adult neural progenitor cells is still unknown. Therefore, we investigated the proliferation of neural progenitor cells from the subventricular zone of adult mice in response to TWEAK treatment. TWEAK inhibited proliferation of neural progenitor cells through its membrane receptor Fn14. The reduced proliferation was not due to cell death. By using a reporter assay we found that TWEAK activated the transcription factor NF-κB in adult neural progenitor cells. Blockade of NF-κB signaling reversed the inhibition of cell proliferation by TWEAK. In addition, TWEAK induced neuronal differentiation of neural progenitor cells and lowered the expression of hes1, a transcription factor that prevents neuronal differentiation. In adult mice deficient of the TWEAK receptor Fn14, neurogenesis was reduced in the subventricular zone. In conclusion, our data show that TWEAK regulates adult neurogenesis in the subventricular zone by binding to the membrane receptor Fn14 and activating NF-κB.
细胞因子 TWEAK 在大脑中表达，并在脑缺血和其他脑疾病中被诱导。TWEAK 调节祖细胞的增殖和分化，但它对成年神经祖细胞的影响尚不清楚。因此，我们研究了 TWEAK 处理对成年小鼠侧脑室下区神经祖细胞增殖的影响。TWEAK 通过其膜受体 Fn14 抑制神经祖细胞的增殖。增殖减少不是由于细胞死亡引起的。通过使用报告基因检测，我们发现 TWEAK 在成年神经祖细胞中激活转录因子 NF-κB。阻断 NF-κB 信号转导可逆转 TWEAK 对细胞增殖的抑制作用。此外，TWEAK 诱导神经祖细胞向神经元分化，并降低阻止神经元分化的转录因子 hes1 的表达。在缺乏 TWEAK 受体 Fn14 的成年小鼠中，侧脑室下区的神经发生减少。总之，我们的数据表明，TWEAK 通过与膜受体 Fn14 结合并激活 NF-κB 来调节侧脑室下区的成年神经发生。
