% IMPORTANT: The following is UTF-8 encoded. This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.
@PHDTHESIS{Wasser:854577,
author = {Wasser, Yasmine},
othercontributors = {Marquardt, Till and Zimmer-Bensch, Geraldine Marion},
title = {{T}he role of {D}lk1 in the gene regulatory network
underlying motor neuron diversification},
school = {RWTH Aachen University},
type = {Dissertation},
address = {Aachen},
publisher = {RWTH Aachen University},
reportid = {RWTH-2022-09639},
pages = {1 Online-Ressource : Illustrationen, Diagramme},
year = {2022},
note = {Veröffentlicht auf dem Publikationsserver der RWTH Aachen
University; Dissertation, RWTH Aachen University, 2022},
abstract = {Delta-like homologue 1 (Dlk1) has been established as
molecular determinant of motor neuron (MN) functional
diversification. Previous studies in mouse and chicken
embryo revealed Dlk1 dependent gene expression during MN
development, which promotes fast alpha MN subtype
properties. However, previous experiments to identify Dlk1
interaction partners and components of the Dlk1 pathway were
not sufficient to fully resolve the pathway. This thesis
addresses the mechanism through which Dlk1 promotes the fast
alpha MN properties. Based on previous observations, the
major focus of the thesis was hypoxia dependent Dlk1
regulation and its contribution to MN diversification during
embryogenesis. Prior, E12.5 embryos were analysed with
regards to Dlk1 protein expression and the evidence of lower
oxygen conditions, as different oxygen levels could have an
influence during neurogenesis. Dlk1 is influenced by lower
oxygen levels in cancer-dependent gene regulations.
Therefore, Dlk1 might also be influenced by low oxygen
levels during neurogenesis. However, since no meaningful
differences in hypoxia could be observed in the spinal cord
of the embryo, the focus was shifted to MN development in
vitro. Therefore, mouse embryonic stem cells were
differentiated into MNs and analysed. With this approach, a
decrease in the amount of full-length Dlk1 protein could be
observed, triggered by hypoxic stimulation. Next, Dlk1
regulation was also investigated in situ in murine brain
slices. Here, it was possible to verify the effects obtained
in embryonic stem cell-derived MNs. It has been shown, that
full-length Dlk1 protein levels decrease after a hypoxic
stimulus, regardless of the age and gender of the mice. To
further investigate the decrease of Dlk1 protein after
hypoxia, a genetically modified embryonic stem cell line was
used to investigate Dlk1 processing. It was found that Dlk1
undergoes cleavage after hypoxic stimulation. Furthermore,
it could be shown that the cleavage is likely dependent on
the TACE/Adam17 protease. Evidence was found for the nuclear
translocation of the cleaved Dlk1 intracellular fragment
upon hypoxia-mediated cleavage. Taken together, Dlk1 is
cleaved by Adam17 in an extracellular and intracellular
fragment, triggered by an external hypoxic stimulation. The
Dlk1 intracellular fragment in part translocated to the
nucleus, where it could function as a transcriptional co
factor and mediate the gene expression signature implemented
by Dlk1. Further, the thesis analyses if Mmp9 gene
regulation is might be associated with the
hypoxic-stimulated Dlk1-dependent process. Dlk1 processing
in cancer-dependent cell regulation could indicate an
influence on the extracellular matrix reorganisation.
Hereafter, Dlk1 might be involved in the Mmp9 secretion
mediated by hypoxic induction.},
cin = {164310 / 160000},
ddc = {570},
cid = {$I:(DE-82)164310_20160808$ / $I:(DE-82)160000_20140620$},
pnm = {GRK 2416 - GRK 2416: MultiSenses-MultiScales: Neue Ansätze
zur Aufklärung neuronaler multisensorischer Integration
(368482240)},
pid = {G:(GEPRIS)368482240},
typ = {PUB:(DE-HGF)11},
doi = {10.18154/RWTH-2022-09639},
url = {https://publications.rwth-aachen.de/record/854577},
}
guest ::