Determine how telomere dysfunction impacts neuronal function

在这里，我们将：i）定义为什么端粒功能障碍选择性地影响神经发生， 齿状回（DG），ii）我们将定义端粒上神经元丢失的机制 DG的功能障碍为了解释为什么端粒功能障碍选择性地影响神经发生， 齿状回，我们将测试端粒功能障碍选择性地影响 成年出生的颗粒细胞GC由于其延长的成熟阶段。为此我们 产生条件性敲除TRF2小鼠胚胎干细胞，其可分化为 神经元细胞这个系统将使我们能够测试的假设， 分化在对端粒功能障碍的反应中起主要作用。同时，我们将 采用DG分化过程发生改变的小鼠遗传学模型。以限定 DG中端粒功能障碍后神经元丢失的机制，我们将评估 DNA损伤激活和端到端染色体融合的发生利用了我们的 先前的工作旨在剖析对TRF2耗尽的细胞应答。在这个系统中， ATM的耗尽可以消除DNA损伤反应的激活，并且程度较小 在一定程度上，通过p53的耗尽。NHEJ通路的抑制完全消除了 端对端染色体融合。总的来说，这些实验将提供一个更好的 了解端粒在中枢神经系统中的作用，以及更深入地了解 DNA损伤激活导致神经元丢失的分子机制 神经元

Here we will: i) define why telomere dysfunction selectively affects neurogenesis in the dentate gyrus (DG) and, ii) we will define the mechanism of neuronal loss upon telomere dysfunction in the DG. To define why telomere dysfunction selectively affects neurogenesis in the dentate gyrus we will test the hypothesis that telomere dysfunction selectively affects adult-born granule cells GCs due to their prolonged maturation phase. To this end, we generated conditional knockout TRF2 mouse embryonic stem cells that can be differentiated into neuronal cells. This system will allow us to test the hypothesis that the timing of differentiation plays a major role in response to telomere dysfunction. In parallel, we will employ mouse genetics models with alteration in the process of DG differentiation. To define the mechanism of neuronal loss upon telomere dysfunction in the DG we will assess the role of the DNA damage activation and onset of end-to-end chromosome fusions taking advantage of our previous work aimed at dissecting the cellular response to TRF2 depletion. In this system, activation of the DNA damage response can be abolished by depletion of ATM and, to a lesser extent, by depletion of p53. Suppression of the NHEJ-pathway completely abolishes the onset of end-to-end chromosome fusions. Collectively, these experiments will provide a better understanding of the role of telomeres in the CNS as well as a deeper understanding of the molecular mechanism that leads to neuronal loss upon DNA damage activation in neurons.