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Antonella Riccio
Novel mechanisms of gene expression in neuronsOverview The proper wiring of the mammalian nervous system is a task of unique complexity, which requires specific point-to-point connections between billions of neurons. At the heart of this fundamental biological process lies the ability of Once a gene is transcribed, its mRNA must be translated into a protein, which then has to be transported to where it is needed. This transport can be especially challenging in differentiated neurons because the nucleus can be very far away from the final location of the protein: the growth cone of a sensory neuron in a mouse embryo, for example, can be millimetres, or even centimetres away from the cell body. Moreover, the half-life of a newly translated protein is often much shorter than the time required for it to travel along the axon to the growth cone. Therefore, many mRNAs encoding proteins required for either axon growth during development or axonal regeneration after injury must be transported and locally translated in axons. The targeting and translation of many of these RNAs may well be regulated by neurotrophins. Thus, the identification of axonal mRNAs and the signaling pathways that regulate their local translation should help us understand how neurotrophins promote axon growth during development and facilitate nerve regeneration in adults. Research projectsI have chosen to explore two understudied, yet extremely important, aspects of neuronal gene expression: the epigenetic modifications that influence gene transcription in developing neurons and the targeting and local translation of mRNAs in axons of neurotrophin-dependent neurons. We recently showed that nitric oxide (NO) influences CREB-dependent transcription by directly nitrosylating histone deacetylase 2 (HDAC2) and thereby altering chromatin acetylation. We have now found that neurorotrophins induce HDAC2 nitrosylation and have identified the cysteines in HDAC2 that are modified by NO. These exciting findings offer a wealth of potential research directions, and we will focus on the following ones. • To characterize the physiological significance of HDAC S-nitrosylation in vitro • To generate knock-in and conditional knock-out transgenic mice • To perform a comprehensive screen to identify the nuclear targets of NO • To identify genes regulated by NO during neuronal development and following behavioural stimulation in vivo
RNA transcripts in axons: a novel approach to unveil mechanisms of regeneration.A second goal of the research in my laboratory is to characterize mRNAs that are locally translated in axons of neurotrophin-dependent neurons and to understand the signalling pathways that regulate their transport. By combining compartmentalized cultures of sympathetic neurons with Sequence Analysis of Gene Expression (SAGE) assays, we have performed an unbiased screen to identify mRNAs localized in axons. We found several hundred, many of which are selectively enriched in axon terminals compared to cell bodies and some of which encode proteins involved in neuronal growth, axon guidance and regeneration. The screen was technically challenging, but we are now in a position to extend the project in several exciting directions, including the following: • To characterize the mRNAs highly enriched in axons • To analyze the role of local protein synthesis for axon growth during development • To identify regulatory sequence(s) that influence mRNA targeting in axons PublicationsMy publication list is maintained and updated dynamically by UCL.
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extracellular cues, such as neurotrophins, to regulate the expression of specific genes that encode proteins that promote neuronal survival, axon growth, differentiation, synapse formation, and, later, synaptic plasticity. Two major regulatory events influence gene expression: binding and activation of nuclear proteins to cis-acting regulatory elements in gene promoters and epigenetic modifications that alter chromatin packing and thereby access of DNA-binding proteins to their DNA sites. While much work has been published on how neurotrophins and other extracellular signals regulate the nuclear factors that control gene expression during neuronal development, surprisingly little is known about the mechanisms by which extracellular cues induce chromatin modifications in these cells. Interestingly, several chromatin-modifying proteins have been associated with neurodegenerative diseases and mental retardation syndromes (the methyl-CpG-binding protein 2 MECP2 with Rett syndrome, and the histone acetylase CBP with Hungtington's Disease and Rubinstein-Taybi syndrome, for example). Understanding how neurotrophins and neurotransmitters induce chromatin remodelling is therefore, of great importance and may provide the rationale for novel treatment strategies. 
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