Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Austria.
Department of Neuropathology, Cluster of Excellence, NeuroCure, Charité - Universitätsmedizin Berlin, Germany.
FEBS J. 2018 Sep;285(17):3175-3196. doi: 10.1111/febs.14603. Epub 2018 Aug 4.
Mice lacking the epidermal growth factor receptor (EGFR) develop an early postnatal degeneration of the frontal cortex and olfactory bulbs and show increased cortical astrocyte apoptosis. The poor health and early lethality of EGFR mice prevented the analysis of mechanisms responsible for the neurodegeneration and function of the EGFR in the adult brain. Here, we show that postnatal EGFR-deficient neural stem cells are impaired in their self-renewal potential and lack clonal expansion capacity in vitro. Mice lacking the EGFR in the brain (EGFR ) show low penetrance of cortical degeneration compared to EGFR mice despite genetic recombination of the conditional allele. Adult EGFR mice establish a proper blood-brain barrier and perform reactive astrogliosis in response to mechanical and infectious brain injury, but are more sensitive to Kainic acid-induced epileptic seizures. EGFR-deficient cortical astrocytes, but not midbrain astrocytes, have reduced expression of glutamate transporters Glt1 and Glast, and show reduced glutamate uptake in vitro, illustrating an excitotoxic mechanism to explain the hypersensitivity to Kainic acid and region-specific neurodegeneration observed in EGFR-deficient brains.
缺乏表皮生长因子受体（EGFR）的小鼠在前脑皮层和嗅球中出现早期的产后退化，并表现出皮质星形胶质细胞凋亡增加。EGFR 小鼠的健康状况不佳和早期致死性阻碍了对导致神经退行性变的机制的分析，以及 EGFR 在成年大脑中的功能。在这里，我们表明，产后缺乏 EGFR 的神经干细胞在自我更新潜力方面存在缺陷，并且在体外缺乏克隆扩增能力。尽管条件等位基因发生了基因重组，但与 EGFR 小鼠相比，大脑中缺乏 EGFR 的小鼠（EGFR ）的皮质退化发生率较低。成年 EGFR 小鼠在机械和感染性脑损伤后会建立适当的血脑屏障并进行反应性星形胶质增生，但对海人酸诱导的癫痫发作更为敏感。缺乏 EGFR 的皮质星形胶质细胞，而不是中脑星形胶质细胞，谷氨酸转运体 Glt1 和 Glast 的表达减少，并且在体外摄取谷氨酸减少，说明了一种兴奋性毒性机制来解释在 EGFR 缺乏的大脑中观察到的对海人酸的敏感性增加和区域特异性神经退行性变。
