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The Journal of Neuroscience, February 22, 2006, 26(8):2207-2214; doi:10.1523/JNEUROSCI.1880-05.2006

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Development/Plasticity/Repair
Myelin Formation during Development of the CNS Is Delayed in Matrix Metalloproteinase-9 and -12 Null Mice

Peter H. Larsen,¹ Angelika Goncalves DaSilva,¹ Katherine Conant,² and V. Wee Yong¹

¹Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada T2N 4N1, and ²Department of Neurology, Johns Hopkins University, Baltimore, Maryland 21205

Correspondence should be addressed to Dr. V. Wee Yong, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, Canada T2N 4N1. Email: vyong{at}ucalgary.ca

The matrix metalloproteinases (MMPs) are implicated in several activities within the nervous system. Although many functions of abnormally elevated MMPs are undesirable, the discrete expression of particular MMP members can have beneficial roles. We previously found that MMP-9 expressed locally around a demyelinating lesion of the spinal cord of adult mice facilitated remyelination. In the current study, we have addressed whether and how MMPs might be required for myelin formation in normal ontogeny. Using a probe for multiple MMPs and the developing mouse optic nerve, we found two members, MMP-9 and -12, to be upregulated during the period of myelin formation. These MMPs partake in myelinogenesis because myelination in the corpus callosum of MMP-9 and/or MMP-12 null mice was deficient from postnatal days 7 to 14 compared with that of wild-type mice. The deficient myelination was correlated with fewer mature oligodendrocytes, but similar precursor cell numbers, in MMP null animals compared with wild type. Because an important growth factor for oligodendrocyte maturation is insulin-like growth factor-1 (IGF-1), we addressed whether this was involved in the deficient myelination in MMP null mice. Indeed, the addition of IGF-1 normalized the lack of maturation of oligodendrocytes that occurred in cultures from MMP-12 null mice. Furthermore, we determined that IGF binding protein 6 (IGFBP-6), which sequesters IGF-1, was a substrate for MMP processing. Finally, we found IGFBP-6 levels to remain high in MMP-deficient mice. These results reveal a novel function for MMP-9 and -12 in developmental myelination likely through regulating IGF-1 bioavailability.

Key words: myelination; matrix metalloproteinase; oligodendrocyte; differentiation; IGF; development

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Received May 11, 2005; revised Dec. 20, 2005; accepted Jan. 15, 2006.

Correspondence should be addressed to Dr. V. Wee Yong, University of Calgary, 3330 Hospital Drive, Calgary, Alberta, Canada T2N 4N1. Email: vyong{at}ucalgary.ca

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