Oligodendrocytes (OLs) extend processes to contact axons as a prerequisite step in myelin formation. As the OL processes migrate toward their axonal targets, they modify adhesion to their substrate, an event that may be regulated by matrix metalloproteinases (MMPs). In the mouse optic nerve, MMP-9/gelatinase B increases during myelin formation. Although tissue inhibitor of metalloproteinase (TIMP)-3 also increases in parallel, the developing optic nerve has focally active MMPs demonstrable by in situ zymography. The distribution of proteolytic activity is similar to that of myelin basic protein, a marker of myelin formation. OLs in culture secrete MMP-9 and express active cell-associated metalloproteinases at the growing tips of their processes. TIMP-1 and a function-perturbing anti-MMP-9 antibody attenuate outgrowth of processes by OLs, indicating a requirement for MMP-9 in process outgrowth. Process reformation is retarded significantly in OLs cultured from MMP-9 null mice, as compared with controls, providing genetic evidence that MMP-9 is necessary for process outgrowth. These data show that MMP-9 facilitates process outgrowth by OLs in vivo and in culture.

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Fibroblast growth factor receptor (FGFR) signaling is essential for nervous system development. We have shown that, in the normal postnatal brain, the spatial and temporal expression pattern of FGFR3 parallels the appearance of differentiated oligodendrocytes and that in culture FGFR3 is expressed maximally at the critical stage in the lineage at which oligodendrocyte late progenitors (Pro-OLs) enter terminal differentiation. Therefore, FGFR3 expression is positioned ideally to have an impact on oligodendrocyte differentiation. In support of this we show that, during the onset and active phase of myelination in FGFR3-deficient mice, there are reduced numbers of differentiated oligodendrocytes in the forebrain, cerebellum, hindbrain, and spinal cord. Furthermore, myelination is delayed in parallel. Delay of oligodendrocyte differentiation also is observed in primary cell culture from this mutant. On the other hand, no differences are observed in the survival or proliferation of oligodendrocyte progenitors. This suggests that the decrease in the number of differentiated oligodendrocytes is attributable to a delay in the timing of their differentiation process. Astrocytes also express FGFR3, and in mice lacking FGFR3 there is an enhancement of the astrocytic marker glial fibrillary acidic protein expression in a region-specific manner. Thus our findings suggest that there are cell type- and region-specific functions for FGFR3 signaling and in particular emphasize a prominent role for FGFR3 as part of a system regulating the onset of oligodendrocyte terminal differentiation.