Kim Jusik, Choi Inseo, Lee Youngsoo
Genomic Instability Research Center, School of Medicine, Ajou University, Suwon, 16499, Republic of Korea.
Department of Biomedical Sciences, The Graduate School, Ajou University, Suwon, 16499, Republic of Korea.
Histochem Cell Biol. 2017 Nov;148(5):489-501. doi: 10.1007/s00418-017-1591-3. Epub 2017 Jun 15.
Maintenance of genomic integrity is one of the critical features for proper neurodevelopment and inhibition of neurological diseases. The signals from both ATM and ATR to TP53 are well-known mechanisms to remove neural cells with DNA damage during neurogenesis. Here we examined the involvement of Atm and Atr in genomic instability due to Terf2 inactivation during mouse brain development. Selective inactivation of Terf2 in neural progenitors induced apoptosis, resulting in a complete loss of the brain structure. This neural loss was rescued partially in both Atm and Trp53 deficiency, but not in an Atr-deficient background in the mouse. Atm inactivation resulted in incomplete brain structures, whereas p53 deficiency led to the formation of multinucleated giant neural cells and the disruption of the brain structure. These giant neural cells disappeared in Lig4 deficiency. These data demonstrate ATM and TP53 are important for the maintenance of telomere homeostasis and the surveillance of telomere dysfunction during neurogenesis.
维持基因组完整性是神经正常发育和抑制神经疾病的关键特征之一。从ATM和ATR到TP53的信号传导是神经发生过程中清除DNA受损神经细胞的众所周知的机制。在这里，我们研究了在小鼠大脑发育过程中，由于端粒重复结合因子2（Terf2）失活导致的Atm和Atr参与基因组不稳定的情况。神经祖细胞中Terf2的选择性失活诱导了细胞凋亡，导致脑结构完全丧失。在Atm和Trp53缺陷小鼠中，这种神经细胞损失得到了部分挽救，但在Atr缺陷背景的小鼠中没有得到挽救。Atm失活导致脑结构不完整，而p53缺陷导致多核巨型神经细胞的形成和脑结构的破坏。这些巨型神经细胞在Lig4缺陷小鼠中消失。这些数据表明，ATM和TP53对于神经发生过程中端粒稳态的维持和端粒功能障碍的监测很重要。
