CDH2_NEUROMIGRATION: The cytoskeleton and Cadherin-2 are tightly linked to coordinate nucleokinesis in migrating neurons.
Project reference: 623612
Duration: From 2015-02-01 to 2017-01-31
Total cost: EUR 161 968,8
EU contribution: EUR 161 968,8
Subprogramme:FP7-PEOPLE-2013-IEF - Marie-Curie Action: "Intra-European fellowships for career development"
Call for proposal:FP7-PEOPLE-2013-IEF
Funding scheme:MC-IEF - Intra-European Fellowships (IEF)
Objective: The cerebellum coordinates the body s movements. It consists of distinct layers of neuronal populations, but during embryonic development, these neurons are generated distantly from their final locations. In zebrafish, this means that cerebellar neurons have to migrate from the upper rhombic lip to the midbrain-hindbrain boundary and further. While descriptions of the migratory pathways for the different neuronal populations have become available in recent years, fundamental questions of this process are still unanswered. Firstly, we currently do not know how guidance of these cells is achieved and translated into directional motility. Activity could be a guiding cue, as it creates intracellular Ca2+-transients which determine directionality in cerebellar neurons. Similarly, depletion of Cadherin-2, a cell-adhesion molecule and key regulator of cell migration, leads to loss of directionality. If activity works through Cadherin-2 to guide cells, it would present a novel way of transmitting information from outside to the inside of cells. We will test this notion using the latest genetic tools. Secondly, Cadherin-2 influences centrosome-positioning, yet we do not know the molecular mechanism of this. IQGAP1 could be the link between Caherin-2 and the microtubules, but this remains to be proven. Thirdly, in order to generate movement of the cells, the forces from the cytoskeleton need to be transmitted to the nucleus. Two models for such mechanisms are being debated, and we will test both in migrating cells in vivo. To address these questions, we will use an interdisciplinary approach combining techniques and knowledge from cell biology, developmental biology and genetics with advanced in vivo time-lapse imaging.Understanding how the cells migration is guided and regulated will improve the fundamental knowledge for the development of therapies for patients suffering from brain injuries or lissencephalies, and create a unique focus of cerebellar research in Europe.
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