Lobanova Anastasia, She Robert, Pieraut Simon, Clapp Charlie, Maximov Anton, Denchi Eros Lazzerini
Department of Molecular Medicine, The Scripps Research Institute, La Jolla, California 92037, USA.
Department of Neuroscience, The Scripps Research Institute, La Jolla, California 92037, USA.
Genes Dev. 2017 Apr 1;31(7):639-647. doi: 10.1101/gad.295402.116. Epub 2017 Apr 20.
Telomeres have been studied extensively in peripheral tissues, but their relevance in the nervous system remains poorly understood. Here, we examine the roles of telomeres at distinct stages of murine brain development by using lineage-specific genetic ablation of TRF2, an essential component of the shelterin complex that protects chromosome ends from the DNA damage response machinery. We found that functional telomeres are required for embryonic and adult neurogenesis, but their uncapping has surprisingly no detectable consequences on terminally differentiated neurons. Conditional knockout of TRF2 in post-mitotic immature neurons had virtually no detectable effect on circuit assembly, neuronal gene expression, and the behavior of adult animals despite triggering massive end-to-end chromosome fusions across the brain. These results suggest that telomeres are dispensable in terminally differentiated neurons and provide mechanistic insight into cognitive abnormalities associated with aberrant telomere length in humans.
端粒在周围组织中已得到广泛研究，但其在神经系统中的相关性仍知之甚少。在这里，我们通过对TRF2进行谱系特异性基因敲除，研究端粒在小鼠大脑发育不同阶段的作用。TRF2是保护染色体末端免受DNA损伤反应机制影响的保护帽复合体的重要组成部分。我们发现，功能性端粒是胚胎期和成年期神经发生所必需的，但令人惊讶的是，其解帽对终末分化神经元没有可检测到的影响。尽管在整个大脑中引发了大规模的端对端染色体融合，但有丝分裂后未成熟神经元中TRF2的条件性敲除对回路组装、神经元基因表达和成年动物行为几乎没有可检测到的影响。这些结果表明，端粒在终末分化神经元中是可有可无的，并为与人类端粒长度异常相关的认知异常提供了机制性见解。
