An Aberrant Cerebellar Development in Mice Lacking Matrix Metalloproteinase-3

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.

Mechanisms of NMDA Receptor- and Voltage-Gated L-Type Calcium Channel-Dependent Hippocampal LTP Critically Rely on Proteolysis That Is Mediated by Distinct Metalloproteinases

“…Such a rapid increase in MMP-3 protein expression after LTP is unsurprising. MMP-3 mRNA is dendritically localized (Suzuki et al, 2007) and undergoes activity-dependent translation in a process that depends on fragile X mental retardation 1 protein and eukaryotic initiation factor 4E (Gkogkas et al, 2014). The process of the fast synaptic translation of MMP-3 mRNA may be similar to MMP-9 (Dziembowska et al, 2012).…”

MMP-3 Deficiency Alleviates Endotoxin-Induced Acute Inflammation in the Posterior Eye Segment

“…Briefly, upon antigen retrieval method with heated citrate buffer (10 mM citric acid, 0.05% Tween 20, pH 6.0), endogenous peroxidases were blocked by incubation in 0.3% H 2 O 2 (in methanol) for 20 min, and subsequently incubated with 20% pre-immune serum before overnight incubation with the primary antibody MMP-3 (1/200, Ab52915, Abcam). Next, Alexa Fluor-conjugated secondary antibodies (Invitrogen) or the TSA TM FITC kit (PerkinElmer, Waltham, MA, USA) were applied as previously published [96,97] and stained sections were examined and photographed using an Olympus FV1000 confocal microscope (Olympus, Berchem, Belgium).…”

Neural patterning of human induced pluripotent stem cells in 3-D cultures for studying biomolecule-directed differential cellular responses

“…The activities of MMPs influence neural progenitor cell proliferation, migration, and lineage commitment [32,[45][46][47][48]. were treated.…”

“…Moreover, dynamic remodeling of extracellular matrices (ECMs) during hiPSC neural differentiation is essential to construct 3-D brain-like tissues with appropriate structure [32,47,54,56]. ECM composition and remodeling, i.e., a balance of ECM secretion and degradation, not only affect cell adhesion sites but also influence signaling pathways that control stem cell fate and tissue development [57,58].…”

“…In particular, MMPs are crucial proteins during ECM remodeling process [58,59]. The activities of MMPs influence neural progenitor cell proliferation, migration, and lineage commitment [32,[45][46][47][48], and were suggested to play a role in long-term brain memory [60,61]. Therefore, understanding dynamic cell-matrix interactions and differential response of neuronal subtypes to MMP inhibition is important to regulate neural tissue development and understand neurological disease pathology.…”