Nikoletopoulou, Vassiliki. Mouse embryonic stem cells as a discovery tool in neurobiology. 2012, PhD Thesis, University of Basel, Faculty of Science.
Official URL: http://edoc.unibas.ch/diss/DissB_9860
In the second part of my thesis, I used this ES cell-based differentiation system to test any potential instructive roles of the 3 neurotrophin tyrosine kinase receptors TrkA, TrkB and TrkC, after recombining them into the neuron-specific mapt locus. This approach led to the surprising observations that TrkA and TrkC cause neuronal death when not activated by their neurotrophin ligands, whereas TrkB does not. Both the death inducing activity of TrkA and TrkC and the lack of death-inducing activity of TrkB were explained by differential distribution of these receptors with p75. The TrkA and TrkC-induced death involves their segregation together with p75 in lipid rafts, and the subsequent proteolysis of the latter signals to the apoptotic machinery. By contrast, TrkB is not recruited to lipid rafts and it does not result in p75 proteolysis. Subsequent analyses of TrkA and ngf mutants, as well as of embryos lacking both TrkA and p75 receptors confirmed the relevance of this novel death triggering mechanism during the development of the peripheral nervous system. These findings also point to a major, and so far un-described, difference in the way growth factors regulate the survival of neurons in the developing peripheral versus central nervous system. It is the receptors themselves that cause neurons to become growth factor dependent in the peripheral, but not in the central nervous system.
Taken together, my results demonstrate that the differentiation of mouse embryonic stem cells into defined neuronal populations represents a useful tool allowing observations to be made that are relevant to the development of the nervous system.
|Committee Members:||Barde, Yves-Alain|
|Faculties and Departments:||05 Faculty of Science > Departement Biozentrum > Neurobiology > Cell Biology (Arber)|
|Bibsysno:||Link to catalogue|
|Number of Pages:||114 S.|
|Last Modified:||30 Jun 2016 10:48|
|Deposited On:||08 May 2012 08:04|
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