Spatiotemporal Expression Patterns of Metalloproteinases and Their Inhibitors in the Postnatal Developing Rat Cerebellum

Abstract

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade the components of the extracellular matrix (ECM). The balance between MMPs and their inhibitors [tissue inhibitors of metalloproteinases (TIMPs)] in the pericellular environment determines the most significant proteolytic events in tissue remodeling. In vitro evidence is accumulating that these molecules may be crucial in the maturation of neural cells. Here, we investigated the in vivo expression of MMPs 2, 3, and 9 and TIMPs 1, 2, and 3 in the developing and adult rat cerebellum using immunohistochemistry and in situ hybridization. During postnatal development, all Purkinje (PK) cell somata expressed all the MMPs and TIMPs studied, whereas their growing dendritic trees expressed only MMP 3 and TIMP 3. In the adult, MMP 3 was confined to PK cell bodies, whereas TIMP 3 was expressed in PK cell somata and processes. Irrespective of the developmental stage, Bergmann glial processes contained only MMP 9, but their somata contained both TIMP 1 and MMP 9. In granular cells, MMPs 3 and 9 and TIMPs 1, 2, and 3 were chiefly detected at a time when migration is known to be maximal; except for that of TIMP 1, their expression persisted in the internal granular layer in the adult. The functional relevance of MMP expression was verified by gelatin zymography. MMP 9 activity was maximal on postnatal day 10 (P10) and was detectable at a low level on P15 and in the adult, whereas MMP 2 activity remained similar throughout postnatal development. Regional and cell-specific expression of MMPs and TIMPs closely reflects the successive stages of cerebellar development, thereby suggesting a pivotal role for ECM proteolysis in brain development and plasticity.

Matrix Metalloproteinase-9 Undergoes Expression and Activation during Dendritic Remodeling in Adult Hippocampus

“…Interestingly, in the developing cerebellum, MMP-9 immunostaining was present in bodies as well as processes of Purkinje neurons, whereas in the adult cerebellum, MMP-9 immunostaining was primarily cytoplasmic. In contrast to our results, Vaillant et al (1999) found that anti-MMP-2 antibody clearly stained cerebellar neurons as well as their dendrites but not glia cells. Other authors have detected MMP-2 protein at axonal growth cones (Zuo et al, 1998).…”

“…Moreover, in Alzheimer's disease, which is associated with significant neuronal cell loss, MMP-9 activity remained unchanged (Lim et al, 1997). Similarly, in developing cerebellum, MMP-9 activity was not elevated at the time of developmental cell death (Vaillant et al, 1999). After kainate treatment, upregulation of MMP-9 protein or mRNA was not detected in degenerating regions.…”

“…Recently, neuronal expression of MMP-9 protein within the rat cerebellum has been reported (Vaillant et al, 1999). Interestingly, in the developing cerebellum, MMP-9 immunostaining was present in bodies as well as processes of Purkinje neurons, whereas in the adult cerebellum, MMP-9 immunostaining was primarily cytoplasmic.…”

Mutant mice with scrambled brains: understanding the signaling pathways that control cell positioning in the CNS

“…Internalization of proteolytic enzymes following receptor activation might modulate cell movement by regulating the function of proteins involved in restructuring the extracellular matrix. This mechanism may be particularly important in the nervous system in which interactions between neurons and the extracellular environment are important during migration, synaptic plasticity, and disease (Sappino et al 1993;Romanic and Madri 1994;Vaillant et al 1999;Yoshida and Shiosaka 1999).…”

Le système MMP/TIMP dans le système nerveux

“…Cet article fait le point sur les résultats récents montrant que les MMP jouent également un rôle central dans la physiopathologie du système nerveux et qu'elles pourraient constituer de nouvelles cibles thérapeutiques dans différentes maladies du système nerveux. < S. Rivera TIMP-1, -2 et -3 et de MMP-2, -3 et -9 sont étroitement liées aux étapes successives du développement postnatal du cervelet [1]. L'expression de MT5-MMP, une MMP membranaire essentiellement exprimée dans le cerveau, varie au cours de l'ontogenèse, avec un pic à la naissance.…”