@phdthesis{Schaefer2005,
  author    = {Sch{\"a}fer, Matthias},
  title     = {Molecular mechanisms of floor plate formation and neural patterning in zebrafish},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-15789},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2005},
  abstract  = {The vertebrate spinal cord is composed of billions of neurons and glia cells, which are formed in a highly coordinated manner during early neurogenesis. Specification of these cells at distinct positions along the dorsoventral (DV) axis of the developing spinal cord is controlled by a ventrally located signaling center, the medial floor plate (MFP). Currently, the origin and time frame of specification of this important organizer are not clear. During my PhD thesis, I have analyzed the function of the novel secreted growth factor Midkine-a (Mdka) in zebrafish. In higher vertebrates, mdk and the related factor pleiotrophin (ptn) are widely expressed during embryogenesis and are implicated in a variety of processes. The in-vivo function of both factors, however, is unclear, as knock-out mice show no embryonic phenotype. We have isolated two mdk co-orthologs, mdka and mdkb, and one single ptn gene in zebrafish. Molecular phylogenetic analyses have shown that these genes evolved after two large gene block duplications. In contrast to higher vertebrates, zebrafish mdk and ptn genes have undergone functional divergence, resulting in mostly non-redundant expression patterns and functions. I have shown by overexpression and knock-down analyses that Mdka is required for MFP formation during zebrafish neurulation. Unlike the previously known MFP inducing factors, mdka is not expressed within the embryonic shield or tailbud but is dynamically expressed in the paraxial mesoderm. I used epistatic and mutant analyses to show that Mdka acts independently from these factors. This indicates a novel mechanism of Mdka dependent MFP formation during zebrafish neurulation. To get insight into the signaling properties of zebrafish Mdka, the function of both Mdk proteins and the candidate receptor Anaplastic lymphoma kinase (Alk) have been compared. Knock-down of mdka and mdkb resulted in the same reduction of iridophores as in mutants deficient for Alk. This indicates that Alk could be a putative receptor of Mdks during zebrafish embryogenesis. In most vertebrate species a lateral floor plate (LFP) domain adjacent to the MFP has been defined. In higher vertebrates it has been shown that the LFP is located within the p3 domain, which forms V3 interneurons. It is unclear, how different cell types in this domain are organized during early embryogenesis. I have analyzed a novel homeobox gene in zebrafish, nkx2.2b, which is exclusively expressed in the LFP. Overexpression, mutant and inhibitor analyses showed that nkx2.2b is activated by Sonic hedgehog (Shh), but repressed by retinoids and the motoneuron-inducing factor Islet-1 (Isl1). I could show that in zebrafish LFP and p3 neuronal cells are located at the same level along the DV axis, but alternate along the anteroposterior (AP) axis. Moreover, these two different cell populations require different levels of HH signaling and nkx2.2 activities. This provides new insights into the structure of the vertebrate spinal cord and suggests a novel mechanism of neural patterning.},
  subject      = {Zebrab{\"a}rbling},
  language  = {en}
}
@phdthesis{Sasi2020,
  author    = {Sasi, Manju},
  title     = {A mouse model for genetic deletion of presynaptic BDNF from adult hippocampal mossy fiber terminals},
  doi       = {10.25972/OPUS-18625},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186250},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Brain-derived neurotrophic factor (BDNF) is a modulator and mediator of structural and functional plasticity at synapses in the central nervous system. Despite our profound knowledge about the synaptic function of BDNF at synapses, it is still controversially discussed whether synaptic BDNF acts primarily from pre- or postsynaptic sites. In the central nervous system, several studies show that mossy fiber (MF) projections formed by hippocampal granule neurons store the highest amount of BDNF. However, immunofluorescence and RNA labelling studies suggest that MF BDNF is primarily produced by granule neurons. Multiple other studies prefer the view that BDNF is primarily produced by postsynaptic neurons such as CA3 pyramidal neurons. Here, we question whether the BDNF, which is stored in the mossy fiber synapse, is primarily produced by granule neurons or whether by other cells in the MF-CA3 microcircuit. After standardization of immunolabelling of BDNF, confocal imaging confirmed the localization of BDNF in presynaptic MF terminals. This anterograde location of synaptic BDNF was also found in distinct regions of the fear and anxiety circuit, namely in the oval nucleus of the bed nucleus stria terminals (ovBNST) and in the central amygdala. To find out whether the presynaptic BDNF location is due to protein translation in the corresponding presynaptic dentate gyrus (DG) granule neuron, we developed and characterized a mouse model that exhibits BDNF deletion specifically from adult DG granule neurons. In this mouse model, loss of presynaptic BDNF immunoreactivity correlated with the specific Creactivity in granule neurons, thus confirming that MF BDNF is principally released by granule neurons. After BDNF deletion from granule neurons, we observed more immature neurons with widely arborized dendritic trees. This indicated that local BDNF deletion also affects the local adult neurogenesis, albeit Cre-mediated BDNF deletion only occur in adult granule neurons. Since BDNF is a master regulator of structural synaptic plasticity, it was questioned whether it is possible to visualize presynaptic, synapse-specific, structural plasticity in mossy fiber synapses. It was established that a combination of Cre-techniques together with targeting of GFP to membranes with the help of palmitoylation / myristoylation anchors was able to distinctly outline the synaptic structure of the BDNF-containing MF synapse. In summary, the mouse model characterized in here is suited to investigate the synaptic signalling function of presynaptic BDNF at the mossy fiber terminal, a model synapse to investigate microcircuit information processing from molecule to behaviour.},
  subject      = {Wachstumsfaktor},
  language  = {en}
}