Vaswani, Ankita Ravi: Function of Reelin Signaling in the Tangential Migration of Dopaminergic Neurons. - Bonn, 2021. - Dissertation, Rheinische Friedrich-Wilhelms-Universität Bonn.
Online-Ausgabe in bonndoc:
author = {{Ankita Ravi Vaswani}},
title = {Function of Reelin Signaling in the Tangential Migration of Dopaminergic Neurons},
school = {Rheinische Friedrich-Wilhelms-Universität Bonn},
year = 2021,
month = jan,

note = {Midbrain dopaminergic neurons (mDA neurons) are involved in the regulation of voluntary movement, reward behavior and cognitive processes. mDA neurons are born in the floor plate of the ventral midbrain, from where they migrate to form three anatomically distinct structures: the laterally positioned substantia nigra (SN), the medially positioned ventral tegmental area (VTA), and the posterior retrorubral field (RRF). Previous studies of the developing mDA system have shown that both SN- and VTA-mDA neurons undergo radial migration between embryonic (E) day 9.5-13.5. Between E12.5 and E15.5, SN-mDA neurons migrate tangentially to separate from the VTA-mDA neurons and take up a more lateral position. However, while the tangential migration of SN-mDA neurons is important for the correct anatomical positioning of the dopaminergic system, little is known about the extracellular signaling cues and dynamic cell morphologies that underlie this process.
The first step in studying migration is visualizing cell movements at high resolution. To provide easy visual access to the neuronal population under investigation, migration is often studied in organotypic slice culture preparations. Migrating mDA neurons form dense clusters in the developing ventral midbrain. In order to study mDA migration in detail, it is therefore essential to mosaically label mDA neurons. Furthermore, to characterize mDA migration, data-analysis protocols need to be developed for tracking a large number of migrating mDA neurons and tracing their cell morphologies in 3D. This study establishes an imaging pipeline for high-resolution 2-photon microscopy of migrating mDA neurons in organotypic slices. Using time-lapse 2-photon images, this study tracks the trajectories, neuronal speeds and cell morphologies of migrating mDA neurons in 3D.
Reelin, an extracellular matrix protein and a well-established regulator of neuronal migration, is known to be important for SN-mDA tangential migration. However, the exact role of Reelin signaling in this process is not completely understood. Disabled 1 (DAB1) is the intracellular mediator of the Reelin signal. The binding of Reelin to its receptors apolipoprotein E receptor 2 (ApoER2) and very low density lipoprotein receptor (VLDLR) activates DAB1 (via phosphorylation). By activating the downstream effectors of Reelin, phosphorylated DAB1 brings about cell adhesion properties and cytoskeletal stability thereby regulating cell migration. In this study, Dab1 was specifically inactivated in differentiated mDA neurons. This resulted in an ectopic medial localization of parts of the SN and an intermingling of SN and VTA-mDA neurons. These data indicate that Reelin signaling is directly required in mDA neurons for their correct localization. Applying the image acquisition and data-analysis pipeline developed in this study to mDA neurons in embryonic organotypic slices from control and Dab1-/- (Dab1 knockout) mice, the speeds, trajectories and underlying cell morphologies of mDA neurons were examined in the presence and absence of Reelin signaling. Using these techniques, this study characterizes the migratory modes and morphological changes underlying SN-mDA tangential migration and demonstrates that Reelin promotes laterally-biased movements in mDA neurons during their slow migration mode. Furthermore, Reelin stabilizes leading process morphology and increases the probability of fast, laterally-directed migration of mDA neurons.
Overall, this study characterizes in detail the migratory and cell morphological characteristics of developing mDA neurons and elucidates the complex role of Reelin in modulating mDA neuronal speed, migratory trajectory and dynamic cell morphology.},

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