Signalling from Endosomes in Neurodevelopment and Neurodegenerative Disorders

by Ronja Markworth
Doctoral thesis
Date of Examination:2021-09-20
Date of issue:2021-11-15
Advisor:Dr. Katja Burk
Referee:Dr. Katja Burk
Referee:Prof. Dr. Silvio O. Rizzoli
Persistent Address: http://dx.doi.org/10.53846/goediss-8920

 

 

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Abstract

English

The nervous system is developed under the regulation of growth and guidance cues. This process is highly dynamic and tightly regulated by the composition, concentration and timely presence of different signalling molecules. whose interactions result in a variety of responses that are complex and specific. For these few, general signalling molecules to elicit so many differential responses, their signals must be integrated and a level of intracellular control for signal integration and differentiation must be in place. The endosomal system with its different organelles characterized by distinct sets of proteins associated is the ideal platform to implement signal diversity. In this thesis I investigate how the endosomal system regulates receptor signalling in axonal growth and degeneration. In the first chapter I give an introduction into the mechanisms of neurodevelopment and signalling of neurotrophic factors, as well as the endosomal system and its involvement in neurodegenerative disorders. In chapter two I present my first project, in which we investigated the principle of signal integration during neurodevelopment. We show that two unrelated receptors , stimulated by two different ligands localize to the same endosomes and spatiotemporally integrate their signal on a shared signalling node to induce neuronal growth. In chapter three I present my second project, in which we have shown that a neurotrophic receptor is retrieved from vacuolar late endosomes by tubular microdomains, thus enabling proper signalling in sensory neurons. We also show how this mechanism is disrupted in neurodegenerative disorder Charcot-Marie-Tooth 2B. In chapter four I discuss how both of these studies highlight the importance of receptor signalling from endosomes and the receptor’s location being tightly controlled. I present other studies that contribute to the image of the endosomal system as a regulator of intracellular signalling and point out caveats in the interpretation of such results.
Keywords: neurodevelopment; neurodegenertaion; CMT2B; Rab7
 
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