Profiling of NGF regulated microRNAs in PC12 cells identifies potential new mediators of neuronal differentiation, plasticity and neuroprotection
Neurotrophins (NGF, BDNF, NT3, NT4/5) regulate neuronal development, survival, dendritic
and axonal growth, synaptic transmission and long-term potentiation. Alterations in their
function are presumably involved in mood disorders and neurodegenerative diseases such
as Alzheimers. microRNAs (miRNAs) - small non-coding RNAs that control the translation of
target messenger RNAs - were shown to regulate critical aspects of neuronal development,
plasticity and disease. To elucidate miRNA regulation by neurotrophins, we profiled - by
microarrays and Real Time PCR - miRNA expression in PC12 cells, which differentiate
into mature neurons when exposed to NGF. miRNA expression was measured at various
times of NGF treatment. The expression of only a small number of miRNAs was clearly
modulated by NGF, some appearing to be induced (e.g. miR-21, miR-207, miR-212), others
repressed (e.g. miR-93, miR-29c, miR-30c). Notably, the promoter regions of miR-207 and
miR-212 have CREB binding sites - a transcription factor representing a major mediator of
neurotrophin signalling, indicating that they are direct NGF signalling mediators. Pathway
enrichment analysis on presumptive targets suggests that NGF modulated miRNAs may
play roles in neuronal signaling and neuronal degeneration. In particular some of them may
be involved in cell survival following NGF deprivation. The overexpression of one of those
miRNAs permitted us to investigate the effect of the overexpression on the neural survival and the amyloidogenic pathway. In conclusion, we have identified a set of microRNAs whose expression is modulated by NGF and may be implicated in neuronal differentiation and plasticity.