%0 Generic
%A Aksan, Bahar
%C Heidelberg
%D 2025
%F heidok:34907
%K Neuroscience, VEGFD, ezrin, STEP, neuronal morphology, plasticity
%R 10.11588/heidok.00034907
%T Molecular mechanisms of neuronal structural maintenance and plasticity
%U https://archiv.ub.uni-heidelberg.de/volltextserver/34907/
%X Dendrites receive and process synaptic inputs and thereby coordinate the connections and wiring   between neurons which is essential for appropriate brain function. Dendritic structural plasticity is   essential throughout development, however in adulthood, dendrites are stabilized and maintained   to survive for years, if not throughout a neuron’s lifetime, to preserve optimal brain circuitry and   cognitive function. Nevertheless, a degree of structural plasticity remains within mature neurons,   allowing adaptation to diverse stimuli and experiences. Imbalances in the equilibrium between   structural plasticity and stability, such as atrophy or maladaptive plasticity, have been implicated in   various neurological disorders. Despite the significance of this delicate balance, the understanding of   molecular and cellular mechanisms governing it remains limited. Vascular Endothelial Growth Factor   D (VEGFD) is a crucial factor in preserving dendrite morphology of mature neurons. However, its   participation in the context of structural plasticity remains uninvestigated. Moreover, its   downstream signaling pathways and how they affect the neuronal cytoskeleton to preserve   dendrites is unknown.  This thesis shows that VEGFD expression is low in developing or adult neurons during activity-induced structural plasticity to allow morphological changes of dendrites. Employing time-lapse   imaging coupled with machine-learning tracking of dendrites, I demonstrated that VEGFD achieves   this by maintaining the existing morphological state of neurons, through limiting dendrite elongation   and destabilizing newly formed dendrites. Furthermore, I characterized the functions of ezrin and c-Raf in dendrite morphology, two cytoskeleton-related proteins identified as potential downstream   targets of VEGFD signaling through phospho-proteomic screening. Using both pharmacological and   genetic tools, I demonstrated that VEGFD causes the dephosphorylation of ezrin at tyrosine 478 via   activation of the striatal-enriched protein tyrosine phosphatase (STEP). Further, I showed through   overexpression of a phospho-mutant ezrin that ezrin is a mediator of the VEGFD-induced   preservation of dendrite structure during structural plasticity. Additionally, immunoprecipitation of   VEGFD's receptor followed by mass spectrometry revealed the splicing regulator neuro-oncological   ventral antigen 2 (nova2) as a potential candidate protein in VEGFD signaling, offering a new path for   future research.   Overall, this work identified the downstream molecular and cellular processes of VEGFD signaling in   plasticity and proposes that VEGFD regulates the balance between neuronal structural maintenance   and plasticity by suppressing morphological alterations in dendrites.