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Casein kinase 2 controls synapse organization and stability

Bulat, Victoria. Casein kinase 2 controls synapse organization and stability. 2013, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10380

Abstract

Synapse remodeling is a local and dynamic process, requiring constant modifications of the neuronal network. Post-translational modifications, such as reversible phosphorylation by kinases and phosphatases, play a crucial role in synapse development and stabilization (Caroni et al., 2012; Wu et al., 2010). To better understand the complex regulation of synaptic stabilization, I performed an unbiased genome-wide RNAi screen consisting of 312 kinases and 127 phosphatases or their subunits. Seven kinases and four phosphatases not previously implicated in synapse stability were identified. They control synapse stability through modulation of phospholipid signaling, metabolic signaling, or the cytoskeleton. The analysis of a major regulatory molecule identified in the screen Casein Kinase 2 (CK2) provides novel insights into the mechanisms controlling the regulation of synapse stability.
CK2 is largely conserved and constitutively active, consisting of two catalytic CK2a and two regulatory CK2b subunits. I demonstrated that both kinase-active CK2a and regulatory CK2b are indispensable for synapse stability pre- but not postsynaptically at the Drosophila neuromuscular junction (NMJ). Moreover, CK2a-CK2b interaction is necessary for the maintenance of stable synapses in vivo demonstrating that CK2 functions as an a2/b2 holoenzyme. I identified essential residues in CK2a that mediate this interaction. In addition, I showed that presynaptic CK2a activity regulates synaptic domain organization and localization of essential synaptic proteins such as the cell adhesion molecule Neuroglian (Nrg) and the adaptor molecule Ankyrin2 (Ank2). Ank2 provides a regulatable link between synaptic cell adhesion molecules and the actin and microtubule cytoskeleton. I demonstrated that CK2 phosphorylates Ank2 in vitro and controls synapse stability at least partially via Ank2, but not via its interaction with Protein Phosphatase 2A (PP2A). Therefore, Ank2L represents an essential substrate of CK2 to regulate synaptic morphology and stabilization. CK2 may thus be an important protein kinase whose function is to control synapse stability through constitutive phosphorylation of structural synaptic components. This provides a compelling mechanism to regulate the lifetime of synaptic connections and to enable local structural synaptic plasticity without disruption of neuronal circuit architecture.
Advisors:Arber, Silvia
Committee Members:Reichert, Heinrich
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Cell Biology (Arber)
Item Type:Thesis
Thesis no:10380
Bibsysno:Link to catalogue
Number of Pages:148 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:53
Deposited On:25 Jun 2013 09:05

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