The flexible nature of neurons is regulated by a complex molecular machinery coupling gene expression to neuronal activation and epigenetic mechanisms are now emerging as key regulators of such process. Neuronal LSD1-8a (Lysine Specific Demethylase 1 including exon E8a) is a mammal restricted neurospecific isoform of the histone demethylase LSD1 generated by alternative splicing. Neuronal LSD1-8a displays demethylase activity on mono- and di-methylated H3-Lys4 and unique pro-maturation properties in cortical neurons. Structural analysis of the protein showed that in neuronal LSD1-8a, the amino acids coded by exon E8a form a loop protruding from the amino oxidase domain in close proximity to the substrate entry site. We discovered that in the brain, this loop contains a threonine phosphorylation site required for the pro-maturation effect. Indeed, in cortical neurons exon E8a phosphorylation is pivotal to induce neurite outgrowth, ampering the transcriptional repressive activity of neuronal LSD1-8a. Post-translational modification of LSD1 represents therefore a dynamic regulatory mechanism in response to neuronal activity. During development we observed that the amount of neuronal LSD1-8a is post-transcriptionally definened by alternative splicing in a highly dynamic fashion. In adult mice a steady level is reached and maintained constant in resting conditions. We present in vivo evidence that pharmacologically induced neuronal activation, is able to affect the ratio of LSD1/LSD1-8a, and that brain specific splicing factors regulate this process. Our data suggest that levels of the pro-maturation phospho-LSD1-8a isoform are dually regulated in response to neuronal stimuli.

Post-transcriptional and post-translational regulation of LSD1 epigenetic activity modulates morphogenesis in neurons / F. Rusconi, L. Paganini, E. Toffolo, C. Verpelli, C. Sala, E. Battaglioli. ((Intervento presentato al convegno FENS, Federation of European Neurosciences tenutosi a Barcelona nel 2012.

Post-transcriptional and post-translational regulation of LSD1 epigenetic activity modulates morphogenesis in neurons

F. Rusconi;L. Paganini;E. Toffolo;E. Battaglioli
2012-07

Abstract

The flexible nature of neurons is regulated by a complex molecular machinery coupling gene expression to neuronal activation and epigenetic mechanisms are now emerging as key regulators of such process. Neuronal LSD1-8a (Lysine Specific Demethylase 1 including exon E8a) is a mammal restricted neurospecific isoform of the histone demethylase LSD1 generated by alternative splicing. Neuronal LSD1-8a displays demethylase activity on mono- and di-methylated H3-Lys4 and unique pro-maturation properties in cortical neurons. Structural analysis of the protein showed that in neuronal LSD1-8a, the amino acids coded by exon E8a form a loop protruding from the amino oxidase domain in close proximity to the substrate entry site. We discovered that in the brain, this loop contains a threonine phosphorylation site required for the pro-maturation effect. Indeed, in cortical neurons exon E8a phosphorylation is pivotal to induce neurite outgrowth, ampering the transcriptional repressive activity of neuronal LSD1-8a. Post-translational modification of LSD1 represents therefore a dynamic regulatory mechanism in response to neuronal activity. During development we observed that the amount of neuronal LSD1-8a is post-transcriptionally definened by alternative splicing in a highly dynamic fashion. In adult mice a steady level is reached and maintained constant in resting conditions. We present in vivo evidence that pharmacologically induced neuronal activation, is able to affect the ratio of LSD1/LSD1-8a, and that brain specific splicing factors regulate this process. Our data suggest that levels of the pro-maturation phospho-LSD1-8a isoform are dually regulated in response to neuronal stimuli.
Settore BIO/13 - Biologia Applicata
Post-transcriptional and post-translational regulation of LSD1 epigenetic activity modulates morphogenesis in neurons / F. Rusconi, L. Paganini, E. Toffolo, C. Verpelli, C. Sala, E. Battaglioli. ((Intervento presentato al convegno FENS, Federation of European Neurosciences tenutosi a Barcelona nel 2012.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/207540
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