Determine how telomere dysfunction impacts neuronal function

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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.