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Tubulin post-translational modifications and microtubule associated proteins in neural development and disease.
Belyaeva, Polina ; Balaštík, Martin (advisor) ; Siahaan, Valerie (referee)
Microtubules (MTs) are essential components of the cytoskeleton in all eukaryotic cells. Their function is particularly important in neurons where MTs stabilize their long processes and are responsible for the precisely regulated anterograde and retrograde, intra-axonal and intra- dendritic transport over long distances. MTs are essential also during development of the vertebrate brain and all its major steps: neurogenesis, neuronal migration and neuronal differentiation. MTs are regulated at multiple levels, but two seem to be particularly important: 1. posttranslational modifications of tubulin (PTMs) have been shown to control several MT properties as stability or MT-based transport. 2. microtubule-associated proteins (MAPs) that bind soluble MT subunits, MT lattice as well as MT ends and control MT-based transport and MT dynamics by either stabilizing, destabilizing or severing MTs. Consequently, deregulation of either tubulin PTMs or MAPs may induce severe changes in neuronal cytoskeleton. Bachelor's thesis summarizes current knowledge on how PTMs (especially polyglutamylation) and MAPs (especially microtubule cleaving proteins such as spastin) regulate MT and neuronal development and degeneration. Keywords: Microtubules, tubulin post-translational modifications, polyglutamylation,...
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The role of CRMP2 in the nervous system development.
Žiak, Jakub ; Balaštík, Martin (advisor) ; Jiruška, Přemysl (referee) ; Horák, Martin (referee)
Regulation of axon guidance and pruning of inappropriate synapses is key to development of neural circuits. Secreted semaphorins are integral part of both processes. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating Semaphorin 3A (Sema3A) signaling, however, nothing is known about its role in the synapse pruning. Similarly, it is also not known if CRMP2 mediates signals from other semaphorins. We herein studied CRMP2 protein and revealed its role in growth and pruning of selected axons and dendrites. In newly generated crmp2-/- and crmp2a-/- mice we demonstrate that CRMP2 has a moderate effect on Sema3A-dependent axon guidance in vivo, and its deficiency leads to a mild defect in axon guidance in peripheral nerves and corpus callosum. CRMP2A isoform is specifically involved in development of callosal axons. Surprisingly, we show that crmp2-/- mice display prominent defects in stereotyped axon pruning in hippocampus and visual cortex and altered dendritic spine remodeling, which are consistent with impaired Sema3F signaling and with models of autism spectrum disorder (ASD). Indeed, we demonstrate that CRMP2 mediates Sema3F signaling in primary neurons and that crmp2-/- mice display ASD-related social behavior changes in early postnatal period as well...
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