Matrix metalloproteinase-9/gelatinase B is required for process outgrowth by oligodendrocytes

Oligodendrocytes (OLs) extend processes to contact axons as a prerequisite step in myelin formation. As the OL processes migrate toward their axonal t argets, they modify adhesion to their substrate, an event that may be regul ated by matrix metalloproteinases (MMPs). In the mouse optic nerve, MMP-9/g elatinase B increases during myelin formation. Although tissue inhibitor of metalloproteinase (TIMP)-3 also increases in parallel, the developing opti c nerve has focally active MMPs demonstrable by in situ zymography. The dis tribution of proteolytic activity is similar to that of myelin basic protei n, a marker of myelin formation. OLs in culture secrete MMP-9 and express a ctive cell-associated metalloproteinases at the growing tips of their proce sses. TIMP-1 and a function-perturbing anti-MMP-9 antibody attenuate outgro wth of processes by OLs, indicating a requirement for MMP-9 in process outg rowth. Process reformation is retarded significantly in OLs cultured from M MP-9 null mice, as compared with controls, providing genetic evidence that MMP-9 is necessary for process outgrowth. These data show that MMP-9 facili tates process outgrowth by OLs in vivo and in culture.