Abstract
Cell–cell and cell–matrix interactions are necessary for neuronal patterning and brain wiring during development. Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of remodelling the pericellular environment and regulating signaling pathways through cleavage of a large degradome. MMPs have been suggested to affect cerebellar development, but the specific role of different MMPs in cerebellar morphogenesis remains unclear. Here, we report a role for MMP-3 in the histogenesis of the mouse cerebellar cortex. MMP-3 expression peaks during the second week of postnatal cerebellar development and is most prominently observed in Purkinje cells (PCs). In MMP-3 deficient (MMP-3−/−) mice, a protracted granule cell (GC) tangential migration and a delayed GC radial migration results in a thicker and persistent external granular layer, a retarded arrival of GCs in the inner granular layer, and a delayed GABAergic interneuron migration. Importantly, these neuronal migration anomalies, as well as the consequent disturbed synaptogenesis on PCs, seem to be caused by an abnormal PC dendritogenesis, which results in reduced PC dendritic trees in the adult cerebellum. Of note, these developmental and adult cerebellar defects might contribute to the aberrant motor phenotype observed in MMP-3−/− mice and suggest an involvement of MMP-3 in mouse cerebellar development.
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Acknowledgements
The authors thank Lut Noterdaeme, Ingrid Proven, Willy Van Ham, Ria Van Laer, and Julie Nys for their technical assistance, Marijke Christiaens for help with the art work, and Lut Arckens and Marc Tjwa for critical reading. This study was supported by grants from the Flemish Institute for the promotion of scientific research (IWT), the Research Council of K.U. Leuven, and the Research Foundation Flanders (FWO), all from Belgium. Inge Van Hove is a fellow of the Flemish Institute for the promotion of scientific research (IWT), Belgium.
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Van Hove, I., Verslegers, M., Buyens, T. et al. An Aberrant Cerebellar Development in Mice Lacking Matrix Metalloproteinase-3. Mol Neurobiol 45, 17–29 (2012). https://doi.org/10.1007/s12035-011-8215-z
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DOI: https://doi.org/10.1007/s12035-011-8215-z