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Title: A defective cerebellar morphogenesis in mice deficient for matrix metalloproteinase-3.
Other Titles: Een foutieve cerebellaire morfogenese in matrix metalloproteïnase-3 deficiënte muizen.
Authors: Van Hove, Inge
Issue Date: 12-Mar-2012
Abstract: Matrix metalloproteinases (MMPs) belong to a large family of endopeptidases able to cleave all matrix proteins and to (in)activate important signaling molecules. As such, MMPs contribute to a wide variety of biological processes, both under physiological and pathophysiological circumstances. Besides their frequently reported detrimental role in neurological diseases, it is becoming increasingly clear that these proteinases are also supporting development, functioning and repair in the central nervous system (CNS). As MMPs can be both friends and foes in the CNS, the challenges for a better understanding of the MMP biology in specific conditions are considerable, especially in order to wisely apply non-selective/selective MMP inhibitors as potential therapeutic drugs. MMP-3 has a very broad degradome, indicating its importance in mediating a wide range of processes. Importantly, MMP-3 has been shown to contribute to many pathologies such as cancer, asthma and rheumatoid arthritis and has also been associated with neurodegenerative diseases. As such, MMP-3 supports neuroinflammation and neuronal apoptosis and contributes to the pathogenesis of Parkinson’s and Alzheimer’s disease. However, MMP-3 also seems to be involved in neurite outgrowth, axonal guidance and plasticity in the CNS. To further unravel a role for MMP-3 in brain development and neuronal wiring, we choose the cerebellar cortex as model system, mainly because of its rather simple anatomy and well-known circuitry. MMP-2, -3, -9 and MT5-MMP are known to be expressed in the developing rat cerebellum, yet, only MMP-9 has been functionally investigated in more detail. Here, we aimed to analyse the spatiotemporal expression pattern of MMP-3 during postnatal mouse development and to characterize a possibly altered cerebellar phenotype and behavior in mice deficient for MMP-3. Moreover, we tried to define the molecular mechanisms via which MMP-3 regulates neural pattern formation and wiring in the mouse cerebellum.RT-PCR and immunohistochemistry revealed increased MMP-3 mRNA and protein levels from the second postnatal week on, with most prominent staining in Purkinje cells (PCs). Histomorphometric investigations showed, from postnatal day 8 (P8) on, a thicker external granular layer (EGL) and an increased number of granule cells (GCs) in the EGL of MMP-3-/- cerebella, as compared to wild-type (WT) cerebella. No abnormalities in GC proliferation or GC apoptosis in the EGL were found. BrdU pulse studies combined with TAG-1 and p27 immunostainings revealed a stalling of radially migrating GCs in the deeper EGL between P6 and P8. In addition, prolonged parallel fibers and an increased number of migrating GCs, processes which possibly underlie the delayed radial GC migration, were found in ex vivo cerebellar explant cultures, harvested from MMP-3-/- mice. These GC migration anomalies, which result in a thicker and persistent EGL in MMP-3-/- mice, as well as the consequent disturbed synaptogenesis of GCs on PCs, seemed to be caused by an abnormal PC dendritogenesis. Indeed, although no overt abnormalities were found in PC number, alignment and soma diameter, detailed analysis of PC morphology revealed a defective dendritogenesis. More specifically, the PC primary dendrite length and tree size were reduced during development, resulting in an aberrant PC morphology in adulthood. Of note, the delayed GC arrival in the internal granular layer (IGL) and the abnormal PC dendritic development resulted in a delayed interneuron migration, a retarded synaptogenesis on PCs and a sustained GC proliferation rate at later stages during cerebellar development in MMP-3-/- animals. Importantly, the observed anatomical developmental alterations were accompanied by mild deficits in balance and motor behavior in postnatal and adult MMP-3-/- mice. In order to define the mechanisms underlying the observed developmental defects in the MMP-3-/- cerebella, a proteomic study was initiated. Data obtained from a 2D-DIGE experiment on P8 cerebellar extracts revealed multiple differential spots, which are currently awaiting identification by mass spectrometry. In conclusion, the results obtained in this study have shed some new light on the involvement of MMP-3 in the development of the postnatal cerebellar cortex, thereby supporting the increasing evidence for a functional role of MMP-3 in neuronal development and wiring. Besides its more frequently reported role in neurodegeneration, these data may stimulate further research investigating the beneficial involvement of MMP-3 in the developing and injured CNS.
ISBN: 978-90-8649-505-4
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Research Group Neural Circuit Development and Regeneration (-)
Animal Physiology and Neurobiology Section - miscellaneous

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