Carlos Wilson
CONICET - Instituto Universitario de Ciencias Biomédicas de Córdoba
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Symposia
Wed 20 | 14:00 - 16:00
Bridging the epigenetic landscape with axonal dynamics: transcriptional and translational concepts for development and repair.
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Axonal growth is a highly dynamic phenomenon, supported by morphological and biochemical transformations throughout the life of neurons. It starts early in newborn neurons, defining the axon-dendritic compartments, and determines the neurotransmission capacity of the mature neuron. Briefly, growing axons requires specification, extension, pathfinding, and maturation. Moreover, further processing, such as myelination, may be needed to improve neurotransmission. Up to date, several mechanisms controlling axonal growth have been reported, mostly affecting cytoskeleton, trafficking, and axon-glia communication. Nevertheless, genetic regulation has remained understudied.
Recent evidence suggests that histone post-translational modifications (PTM) and non-coding RNAs (ncRNAs) are novel epigenetic players strongly linked to axonal growth in health and disease. Therefore, this symposium will be focused on their role in axonal specification, guidance and maturation. In addition, we will discuss the influence of PTMs on axonal recovery after lesions, such as spinal cord injury. Finally, we will approach the therapeutic potential of extracellular vesicles released by stem cells carrying miRNAs, and their role on axonal regeneration capacity and myelination of neurons.
Speakers
Epigenetic regulation of neuronal polarization and axon growth by the histone methyltransferase G9a and the H3K9me2 label
Carlos Wilson
CONICET - Instituto Universitario de Ciencias Biomédicas de Córdoba
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Neurons are polarized cells, exhibiting the somato-dendritic and axonal compartments; domains specialized in receiving and transmitting signals, respectively. This compartmentalization is the result of decoding extrinsic/intrinsic stimuli, impacting on signaling pathways able to shape the neuronal morphology. In this regard, cytoskeleton remodeling is crucial, since both microtubules (MT) and F-actin (FA) represent the driving force of polarization and axonal development. Although polarity mechanisms have been reported, the genetic fundamentals remain underexplored. Recently, we reported that the histone methyltransferase G9a promotes polarization and axonal growth in cultured hippocampal neurons, by repressing the RhoA-ROCK pathway, a negative regulator of neuronal polarization. In addition, the loss of function of G9a in situ impaired cortical migration of embryonic neurons, suggesting failures on polarization and migration in vivo. Moreover, bi-methylation of H3K9 (H3K9me2), highly dependent on G9a in developing neurons, parallels axon formation in early and mature stages. Accordingly, genetic deletion of nuclear H3K9me2 impairs axonal maturation, visualized by abnormal assembly of the axon initial segment (AIS); the intra-axonal domain in which voltage-dependent ion channels are recruited. Overall, our results suggest a link between epigenetic regulation and axonal development in central neurons through a G9a-H3K9me2 – dependent mechanism.
ncRNAs: a non-canonical mode of intracellular transport through organelle hitchhiking
Marie-Laure Baudet
University of Trento
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Most cells are polarized with an intracellular milieu that is not homogenous but partitioned. mRNA localization and its corollary, local translation, are key mechanisms to create and sustain polarity by conferring functional autonomy to a variety of subcellular compartments. Recent evidence suggests that not only mRNAs but also various regulatory RNAs, such as miRNAs and circular RNAs, are localized to and enriched within subcellular outposts. The mechanisms of ncRNA transport to these compartments remain, however, elusive. This is largely due to the lack of adequate tools to study ncRNA trafficking.
We developed labeled nucleic-acid-based approaches to track diverse types of endogenous ncRNAs through live imaging. To achieve this, we exploited the specific features of each ncRNA type under study including their unique sequence and secondary structure. We applied these tools to investigate ncRNA trafficking specifically within axons of the highly polarized neurons as a model subcellular compartment.
We uncovered that specific ncRNA species employ a unique mode of transport that relies on organelle hitchhiking. Organelles, in turn, deliver ncRNAs to their site of function. Overall, our results reveal critical insight into the molecular mechanisms of ncRNA subcellular localization. They also provide fundamental knowledge of axonal transport, a process derailed in several incurable neurodegenerative disorders, with potential future therapeutic application
Targeting the CBP/p300 acetyltransferase with a small-molecule activator to enhance axon regeneration and functional recovery after spinal cord injury
Thomas Hutson
Swiss Federal Institute of Technology (EPFL)
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Injured axons fail to regenerate in the adult mammalian central nervous system (CNS) leading to permanent deficits in sensorimotor function. We have shown that increasing the activity of proprioceptive dorsal root ganglion (DRG) neurons using an enriched environment induces a long-lasting increase in their regenerative potential that is dependent on CREB Binding Protein (CBP) mediated histone acetylation. Systemic application of a pharmacological activator (CSP-TTK21) of the acetyletransferase CBP/p300 acutely after a spinal cord injury (SCI) led to a significant increase in the sprouting of sensory and motor fibres as well as a significant improvement in sensorimotor recovery. Our findings demonstrate the importance of the chromatin environment to the regenerative capacity of neurons. Recovery in chronic injury models is challenging yet could offer huge benefits to patients currently afflicted by SCI. By manipulating key histone modifiers that orchestrate broad changes in gene transcription we aim to further enhance neuroplasticity and achieve significant improvements in axonal sprouting and functional recovery.
Stem Cell-Derived Extracellular Vesicles Promote Regeneration During Demyelination ex vivo
Ana Lis
Centro de Investigación en Medicina Traslacional "Severo Amuchástegui" (CIMETSA) Instituto Universitario de Ciencias Biomédicas de Córdoba (IUCBC)
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Extracellular vesicles (EVs) are a heterogeneous group of nanovesicles that shuttle bioactive molecules (e.g. proteins, lipids and RNAs) and modulate biological functions in recipient cells. EVs secreted by stem cells can promote tissue regeneration and function as potential alternatives to stem cell therapy. Furthermore, EVs have fewer side effects and do not present risks associated with cellular transplants such as incomplete differentiation or tumorigenesis. Recent studies have shown that administration of murine neural stem cells’ EVs (mNSC-EVs) promote regeneration and restore neurological functions in animal models of CNS disorders. However, the molecular mechanisms responsible for these biological effects in the CNS are unknown and it is unclear whether human NSC-EVs promote myelin regeneration. Results from our laboratory indicate that EVs secreted by human induced pluripotent stem cells (hiPSC-EVs) and human neural stem cells (hNSC-EVs) promote myelin regeneration in an ex vivo model of CNS demyelination. Considering that EVs can transfer functional coding and non-coding RNA between cells, we performed in silico analyses of small non-coding RNA profiling data from hiPSC-EVs and hNSC-EVs. We found that EVs secreted by hiPSC and hNSC are enriched in small RNAs that control oligodendrocyte proliferation and differentiation. These results indicate that hiPSC-EVs and hNSC-EVs promote the regeneration of myelin at least in part through the transfer of small RNAs.