CDH2_NEUROMIGRATION · The cytoskeleton and Cadherin-2 are tightly linked to coordinate nucleokinesis in migrating neurons

The cytoskeleton and Cadherin-2 are tightly linked to coordinate nucleokinesis in migrating neurons

Final publishable summary report Executive summary The brain is one of the most complex organs in the human body. Fundamental knowledge about how the brain develops during embryogenesis is still fragmented, as techniques that allow the study of organ development in vivo without interfering with the organism were largely unavailable. The adaptation of sophisticated imaging techniques to rapidly developing embryos from non-mammalian species that naturally occurs outside the body have greatly contributed to closing this gap in our knowledge in recent years. These methods have now made it possible to observe biological phenomen at early stages of brain formation that previously required the surgical intrusion or destruction of the embryos and their parent. One such biological phenomenon is neuronal migration. The brain is a highly complex organ made up from a large number of different cell types that are precisely arranged into regions and layers in order to exert their functions. The spatial arrangement of neurons is created by neuronal migration, which occurs in the early stages of brain formation. Neurons that arise from a cell-creating site (the germinal zone) typically leave this region in a highly time-controlled developmental window along precisely defined routes. As migration organizes the different cell types and brings the correct partners in contact, it is thought that neuronal migration is fundamental to forming a functional brain. While the routes and the main guidance signal that influence the cells have been identified in recent years, we still lack a thorough understanding of how the progress along a given route is controlled in neurons. In our project, we aimed at elucidating whether and how neurotransmitter-mediated activity could act as control mechanism in neuronal migration, using the in vivo migration of tegmental hindbrain nuclei neurons (THNs) in live zebrafish embryos as a model system. Using pharmacological and optogenetic methods, we found that different neurotransmitters regulate the progress of THNs either positively or negatively. We have summarized these results in a model that describes the effects as regions of influence acting in different parts of the cerebellum that the THNs could use to navigate the tissue. Next, we have investigated the molecular basis of the conversion of such (external) signals into active forward movement. In this, we have concentrated on the local distribution of Cadherin-2, which had previously been identified as an important regulator for THN migration. Lastly, we have probed the role of microtubules in neuronal migration as it occurs in its natural surroundings, as current models had proposed a prominent role for this part of the cytoskeleton in force generation in migrating neurons. While we can demonstrate that microtubules are essential to THN migration, contrary to expectations, our results suggest that a regulatory role for microtubules could be more important than force generation, which could be related to its function in the intracellular transport and subcellular distribution of Cadherin-2. This project has yielded valuable insights into the fundamental regulation of neuronal cell migration. As neuronal migration is considered to be essential to the formation of a functional brain, it provides the starting point for future studies into the working of the brain and biomedical applications. Online information and contact details Further information can be found at http://www.zoologie.tu-bs.de/index.php/en/cellular-molecular-neurobiology/research/neuronal-migration Or by contacting the lead scientist or the fellow: Prof. Reinhard Köster Cellular and Molecular Neurobiology Zoological Institute TU Braunschweig Spielmannstr. 7 38106 Braunschweig Germany Email: r.koester@tu-bs.de Dr. Ulrike Theisen Cellular and Molecular Neurobiology Zoological Institute TU Braunschweig Spielmannstr. 7 38106 Braunschweig Germany Email: u.theisen@tu-bs.de

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