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Identification and characterization of cell adhesion molecules controlling synapse stability

Enneking, Eva-Maria. Identification and characterization of cell adhesion molecules controlling synapse stability. 2012, PhD Thesis, University of Basel, Faculty of Science.

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Official URL: http://edoc.unibas.ch/diss/DissB_10211

Abstract

Neuronal circuits form the basis of a functional nervous system to process and integrate information and to react to environmental cues. The formation of functional synaptic connections between neurons is essential for the establishment of these circuits. During development and in response to activity information processing within neuronal circuits is adjusted by the selective addition or elimination of individual synapses. Impairment of synapse stability can lead to the disruption of neuronal circuits and results in severe neurodegenerative diseases. Thus, it is important to understand the molecular mechanisms controlling synaptic maintenance and plasticity.
Trans-synaptic interactions mediated by cell adhesion molecules (CAMs) have the potential to provide a stable connection between two neighboring neurons. Many cell adhesion molecules have been identified controlling the initial steps of neuronal circuit formation such as axon guidance, target recognition and synaptogenesis. However detailed knowledge about the identity and regulation of cell adhesion molecules during synapse stabilization is missing to date.
In this study I used the Drosophila melanogaster larval neuromuscular junction (NMJ) as a model system to identify novel cell adhesion molecules controlling synaptic maintenance in vivo. I performed an unbiased RNAi-based screen targeting entire classes of cell adhesion molecules with potential functions during nervous system development. I identified a number of novel candidates that have the potential to control synapse stabilization and performed a detailed characterization of two genes: neuroglian (nrg) encoding the L1-type CAM and CG31708 (uhu) coding for an Immunoglobulin (Ig) domain protein
The L1-type CAM Neuroglian has the capability to interact with the adaptor protein Ankyrin2 (Ank2), which is part of a molecular network underneath the cell membrane that can control synapse stability by directly coupling CAMs to the presynaptic actin and microtubule cytoskeleton. In addition to Ank2, this network consists of the scaffolding proteins alpha- and beta-Spectrin and the actin capping molecule Hts/Adducin. By combining biochemical, biophysical and genetic assays I demonstrated that the impairment of Ankyrin binding causes an increase in Nrg mobility that correlates with increased synaptic growth but decreased stability. In summary my results provide evidence of a novel regulatory module controlling synapse stability and growth through the regulated interaction between L1-type CAMs and Ankyrins.
Advisors:Pielage, Jan
Committee Members:Reichert, Heinrich and Scheiffele, Peter
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Molecular Zoology (Reichert)
Item Type:Thesis
Thesis no:10211
Bibsysno:Link to catalogue
Number of Pages:197 Bl.
Language:English
Identification Number:
Last Modified:30 Jun 2016 10:51
Deposited On:15 Jan 2013 14:54

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