Ablation of the microRNA-17-92 cluster in neural stem cells diminishes adult hippocampal neurogenesis and cognitive function.

Abstract

Impairment of adult neurogenesis in the hippocampus causes cognitive deficits; however, the underlying molecular mechanisms have not been fully elucidated. microRNAs (miRNAs) regulate neural stem cell (NSC) function. With the use of a transgenic mouse line with conditional ablation of the miR-17-92 cluster in nestin lineage NSCs, we tested the hypothesis that the miR-17-92 cluster regulates adult neurogenesis and cognitive function in vivo. Compared with wild-type mice, ablation of the miR-17-92 cluster significantly reduced the number of proliferating NSCs and neuroblasts and neuronal differentiation in the dentate gyrus (DG) of the hippocampus and significantly impaired hippocampal-dependent learning and memory, as assayed by social recognition memory, novel object recognition, and Morris water-maze tests. Statistical analysis showed a highly significant correlation between newly generated neuroblasts in the DG and cognition deficits in miR-17-92 knockout (KO) mice. Western blot analysis showed that conditional KO of the miR-17-92 cluster significantly increased and reduced a cytoskeleton-associated protein, Enigma homolog 1 (ENH1), and its downstream transcription factor, inhibitor of differentiation 1 (ID1), respectively, as well as increased phosphatase and tensin homolog gene. These proteins are related to neuronal differentiation. Our study demonstrates that the miR-17-92 cluster in NSCs is critical for cognitive and behavioral function and regulates neurogenesis and that the miR-17-92 cluster may target ENH1/ID1 signaling.-Pan, W. L., Chopp, M., Fan, B., Zhang, R., Wang, X., Hu, J., Zhang, X. M., Zhang, Z. G., Liu, X. S. Ablation of the microRNA-17-92 cluster in neural stem cells diminishes adult hippocampal neurogenesis and cognitive function.