Neuronal differentiation by TAp73 is mediated by microRNA-34a regulation of synaptic protein targets

The p53-family member TAp73 is a transcription factor that playsa key role in many biological processes. Here, we show that p73drives the expression of microRNA (miR)-34a, but not miR-34b and-c, by acting on specific binding sites on the miR-34a promoter.Expression of miR-34a is modulated in parallel with that of TAp73during in vitro differentiation of neuroblastoma cells and corticalneurons. Retinoid-driven neuroblastoma differentiation is inhibitedby knockdown of either p73 or miR-34a. Transcript expression ofmiR-34a is significantly reduced in vivo both in the cortex andhippocampus of p73−/− mice; miR-34a and TAp73 expression alsoincrease during postnatal development of the brain and cerebellumwhen synaptogenesis occurs. Accordingly, overexpression or silencingof miR-34a inversely modulates expression of synaptic targets,including synaptotagmin-1 and syntaxin-1A. Notably, the axisTAp73/miR-34a/synaptotagmin-1 is conserved in brains from Alzheimer’spatients. These data reinforce a role for TAp73 in neuronaldevelopment.