Epigenetic and transcriptional regulation of neural development : Scml2 and Ezh2, new functions in health and disease

Loche, Alberto. Epigenetic and transcriptional regulation of neural development : Scml2 and Ezh2, new functions in health and disease. 2015, Doctoral Thesis, University of Basel, Faculty of Science.


Official URL: http://edoc.unibas.ch/diss/DissB_11714

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Neuronal activity is one of the most fascinating and complex properties of living cells, in which a quickly dissolving signal, or a pattern of them, is used to transfer a tremendous amount of information at any given time. This ensemble of signals must be fine tuned through the coupling of this activity patterns with a cell memory system that can ensure neuronal homeostasis and synaptic plasticity in response to mutating stimuli. Epigenetic processes provide an efficient way to transform activity dependent neuronal information into lasting effects on gene expression. Among others, the modification of histones at conserved critical residues is a well described epigenetic mechanism. Polycomb group proteins are some of the major cellular machineries mediating such regulation, and their function has been extensively studied during early phases of development. Nevertheless, their function in post-mitotic neurons is less understood. The broad aim of the present work is to investigate Polycomb protein function in the context of specialized neuronal functions, such as migration and proper establishment of inhibitory synapses. We therefore focused our attention on two proteins, Ezh2 (a Polycomb Repressive complex 2 subunit) and Scml2 (a Polycomb Repressive complex 1 variant member).
Epilepsy represents one of the most prevalent and detrimental neurological diseases, characterized by a disregulation of neuronal activity resulting into unpredictable synchronized waves, or seizures, spreading throughout the central nervous system. Evidences from both animal models and from human brain tissue have started to unveil that epilepsy and epileptogenesis can be associated with epigenetic changes. Aim of this work is to describe a novel epileptic syndrome, that opens a door to a new possible mechanism at the basis of activity disregulation in the brain. SCML2 is a poorly studied gene, which translates into a member of the Polycomb Repressive Complex 1, a master regulator of gene repression and chromatin compaction. By generating mutant mice lacking the SCML2 functional protein, we discovered that its function is important to ensure proper inhibitory inputs onto excitatory neurons. A similar mechanism may be acting in the cortex as well as in the spinal cord, leading to hyperexcitability and the development of synchronous activity upon challenge. Our analysis provides the first case of a Polycomb protein involved in the pathogenesis of human epilepsy and shed some light into a possible whole new field of investigation, where a deeper understanding of such epigenetic processes will likely lead to exciting new discoveries and possible new treatment options for a highly unmet medical need.
Advisors:Rijli, Filippo M. and Sassone-Corsi, Paolo
Faculties and Departments:09 Associated Institutions > Friedrich Miescher Institut FMI > Neurobiology > Transcriptional mechanisms of topographic circuit formation (Rijli)
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:11714
Thesis status:Complete
Number of Pages:1 Online-Ressource (108 Seiten)
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edoc DOI:
Last Modified:01 Jul 2020 12:49
Deposited On:16 Sep 2016 08:06

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