Telomere protection mechanisms change during neurogenesis and neuronal maturation: Newly generated neurons are hypersensitive to telomere and DNA damage
Telomere protection mechanisms change during neurogenesis and neuronal maturation: Newly generated neurons are hypersensitive to telomere and DNA damage
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DOI：
10.1523/jneurosci.0590-07.2007
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发表时间：
2007-04-04
影响因子：
5.3
通讯作者：
Mattson, Mark P.
中科院分区：
文献类型：
--
作者：
Cheng, Aiwu;Shin-ya, Kazuo;Mattson, Mark P.
端粒是真核染色体末端的 DNA-蛋白质复合物，在维持基因组完整性方面发挥着重要作用。在增殖干细胞和癌细胞中，端粒长度由端粒酶维持，端粒结构和功能由端粒相关蛋白调节。我们发现胚胎皮质神经祖细胞（NPC）中端粒酶水平较高，而新生神经元（NGN）和成熟神经元（MN）中端粒酶水平较低。相比之下，端粒重复结合因子 2 (TRF2) 的表达在体内早期大脑发育和培养的 NPC 中检测不到，并且随着 NPC 停止增殖并分化为有丝分裂后神经元，其表达水平逐渐升高。端粒干扰剂端粒抑素会在 NGN（具有低水平的 TRF2 和端粒酶）中诱导 DNA 损伤反应和细胞凋亡，而 NPC（具有高水平的端粒酶）和 MN（具有高水平的 TRF2）对端粒损伤具有抵抗力。 NGN 中 TRF2 的过度表达可以保护它们免受端粒抑素和其他 DNA 损伤剂诱导的死亡。 MN 中 TRF2 表达的敲低和 NPC 中端粒酶逆转录酶的敲除增加了它们对端粒和 DNA 损伤剂的敏感性，但不影响 NGN 的脆弱性。这些发现表明，TRF2 和端粒酶在神经发生和神经元成熟过程中发挥着不同的端粒保护机制，NGN 对端粒损伤的超敏反应是由于端粒酶和 TRF2 的相对缺陷造成的。
Telomeres are DNA-protein complexes at the ends of eukaryotic chromosomes that play an important role in maintaining the integrity of the genome. In proliferative stem cells and cancer cells, telomere length is maintained by telomerase, and telomere structure and functions are regulated by telomere-associated proteins. We find that telomerase levels are high in embryonic cortical neural progenitor cells (NPCs) and low in newly generated neurons (NGNs) and mature neurons (MNs). In contrast, telomere repeat-binding factor 2 (TRF2) expression is undetectable in early brain development in vivo and in cultured NPCs and is expressed at progressively higher levels as NPCs cease proliferation and differentiate into postmitotic neurons. The telomere-disrupting agent telomestatin induces a DNA damage response and apoptosis in NGNs (which have low levels of TRF2 and telomerase), whereas NPCs (which have high levels of telomerase) and MNs (which have high levels of TRF2) are resistant to telomere damage. Overexpression of TRF2 in NGNs protects them against death induced by telomestatin and other DNA-damaging agents. Knockdown of TRF2 expression in MNs and knock-out of telomerase reverse transcriptase in NPCs increased their sensitivity to telomere-and DNA-damaging agents but did not affect the vulnerability of NGNs. These findings suggest that TRF2 and telomerase function as distinct telomere protection mechanisms during the processes of neurogenesis and neuronal maturation and that hypersensitivity of NGNs to telomere damage results from relative deficiencies of both telomerase and TRF2.