Kieweg, Ingrid Daniela. Madm controls synapse development and stability. 2014, PhD Thesis, University of Basel, Faculty of Science.
Restricted to Repository staff only until 16 December 2018.
Official URL: http://edoc.unibas.ch/diss/DissB_11110
Little is still known regarding the molecular control of synapse formation, maintenance and refinement. The Drosophila neuromuscular junction (NMJ) represents an excellent model system to study these mechanisms. To identify novel regulatory molecules controlling synapse development and maintenance, I designed two RNAi-based genetic screens targeting 269 candidate genes. Two groups of proteins were analyzed: cytoskeleton, cytoskeleton-associated and transport proteins as well as signaling molecules from different conserved pathways.
I focused on the analysis of a very promising candidate gene, the Mlf1 adapter molecule (Madm). In this study, we implicate for the first time a central role for Madm in the nervous system. Madm is a pseudo kinase which was previously shown to be an adaptor for unknown growth-related signaling pathways in Drosophila (Gluderer S. et al. 2010). We demonstrate that Madm controls multiple aspects of synapse development and refinement at the Drosophila neuromuscular junction (NMJ). First, Drosophila madm mutants displayed prominent synaptic stability and degeneration defects. Second, Madm mutant animals showed severe morphological alterations as well as reduced growth of NMJs. Third, nerves in Madm mutant animals displayed huge swellings and varicosities - a hallmark of neurodegenerative diseases in mammals and humans e.g. in Parkinson’s and Alzheimer’s disease. Fourth, Madm depletion resulted in the accumulation of the presynaptic marker Bruchpilot (BRP) in motoneuron axons. In addition, we could identify two genetic interaction partners of Madm - Myeloid leukemia factor (Mlf) and Bunched A (BunA). Mlf and BunA mutant animals showed similar tendencies of impaired synaptic stability and morphology. Using genetic interaction studies, we demonstrated that Mlf together with Madm normally promotes synaptic stability at the NMJ whereas BunA antagonizes synaptic instability caused by the loss of Madm.
In conclusion, our findings support a model of Madm - together with BunA and Mlf - acting as a novel platform controlling different aspects of the normal development, growth and maintenance of synapses.
|Committee Members:||Pielage, Jan and Reichert, Heinrich|
|Faculties and Departments:||09 Associated Institutions > Friedrich Miescher Institut FMI > Motor circuit function (Arber)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||172 p.|
|Last Modified:||20 Oct 2016 09:22|
|Deposited On:||02 Feb 2015 13:27|
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