Cadherin-2 Controls Directional Chain Migration of Cerebellar Granule Neurons

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Abstract
Long distance migration of differentiating granule cells from the cerebellar upper rhombic lip has been reported in many vertebrates. However, the knowledge about the subcellular dynamics and molecular mechanisms regulating directional neuronal migration in vivo is just beginning to emerge. Here we show by time-lapse imaging in live zebrafish (Danio rerio) embryos that cerebellar granule cells migrate in chain-like structures in a homotypic glia-independent manner. Temporal rescue of zebrafish Cadherin-2 mutants reveals a direct role for this adhesion molecule in mediating chain formation and coherent migratory behavior of granule cells. In addition, Cadherin-2 maintains the orientation of cell polarization in direction of migration, whereas in Cadherin-2 mutant granule cells the site of leading edge formation and centrosome positioning is randomized. Thus, the lack of adhesion leads to impaired directional migration with a mispositioning of Cadherin-2 deficient granule cells as a consequence. Furthermore, these cells fail to differentiate properly into mature granule neurons. In vivo imaging of Cadherin-2 localization revealed the dynamics of this adhesion molecule during cell locomotion. Cadherin-2 concentrates transiently at the front of granule cells during the initiation of individual migratory steps by intramembraneous transport. The presence of Cadherin-2 in the leading edge corresponds to the observed centrosome orientation in direction of migration. Our results indicate that Cadherin-2 plays a key role during zebrafish granule cell migration by continuously coordinating cell-cell contacts and cell polarity through the remodeling of adherens junctions. As Cadherin-containing adherens junctions have been shown to be connected via microtubule fibers with the centrosome, our results offer an explanation for the mechanism of leading edge and centrosome positioning during nucleokinetic migration of many vertebrate neuronal populations. As the vertebrate nervous system develops, neurons migrate from proliferation zones to their later place of function. Adhesion molecules have been implicated as key players in regulating cellular motility. In addition, the centrosome (the main microtubule organizing center of the cell) orients into the direction of neuronal migration. In this study we assign the trans-membrane adhesion molecule Cadherin-2 with an important function in the migration of granule neurons in the cerebellum, by interconnecting adhesion with directionality of migration. Time-lapse analysis in transparent zebrafish embryos revealed that Cadherin-2 enables granule neurons to form ‘chain’-like structures during migration. In addition, this adhesion molecule stabilized the position of the centrosome at the leading edge of the migrating neuron. In vivo tracing of a fluorescent Cadherin-2 reporter molecule showed that during individual migratory steps of a granule neuron, Cadherin-2 is shifted along the cell membrane in contact with chain-migrating neighboring neurons to the front compartment of migrating cells. Cadherin-2 is a crucial component of adherens junctions, which are connected via microtubules to the centrosome. We propose that the forward translocation of Cadherin-2-containing adherens junctions stabilizes the centrosome to the cell's front. Cadherin-2 thus transmits cell-cell contact modulation into directional migration of cerebellar granule neurons.