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Neurogenesis is a highly-regulated process occurring in the dentate gyrus that has been linked to learning, memory, and antidepressant efficacy. MicroRNAs (miRNAs) have been previously shown to play an important role in the regulation of neuronal development and neurogenesis in the dentate gyrus via modulation of gene expression. However, this mode of regulation is both incompletely described in the literature thus far and highly multifactorial. In this study, we designed sensors and detected relative levels of expression of 10 different miRNAs and found miR-338-3p was most highly expressed in the dentate gyrus. Compari- son of miR-338-3p expression with neuronal markers of maturity indicates miR-338-3p is expressed most highly in the mature neuron. We also designed a viral “sponge” to knock down in vivo expression of miR-338-3p. When miR-338-3p is knocked down, neurons sprout multiple primary dendrites that branch off of the soma in a disorganized manner, cellular pro- liferation is upregulated, and neoplasms form spontaneously in vivo. Additionally, miR-338- 3p overexpression in glioblastoma cell lines slows their proliferation in vitro. Further, low miR-338-3p expression is associated with increased mortality and disease progression in patients with glioblastoma. These data identify miR-338-3p as a clinically relevant tumor suppressor in glioblastoma.
In Plain English:
MicroRNAs are small molecules that turn down the levels of specific genes by preventing them from creating proteins. We found one such microRNA, miR-338-3p, exists at very high levels in the dentate gyrus, one of the only parts of the brain to form new neurons throughout a person’s entire lifespan. When we looked at the neurons in the dentate gyrus that had miR-338-3p, we saw its abundance rise as the neuron developed: the cells that eventually become neurons barely expressed miR-338-3p, newborn neurons contained it at low levels, and mature neurons had high amounts of miR-338-3p. When we removed miR-338-3p from the neuron early in its lifetime, they matured into neurons lacking some aspects of their overall organization, pointing to a role for miR-338-3p important to neuronal development. When we removed miR-338-3p, glioblastomas, the most aggressive form of brain tumor, would also begin to form from the cells that lost the microRNA. When we added miR-338-3p to glioblastoma cells, they would then divide slower. These results show miR-338-3p likely prevents glioblastomas from forming in the brain. Glioblastoma patients in clinic with abnormally low levels of miR-338-3p tend to have worse outcomes as well, so miR-338-3p could be a future target for glioblastoma treatment.