Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and-12 null mice
Myelin formation during development of the CNS is delayed in matrix metalloproteinase-9 and-12 null mice
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DOI：
10.1523/jneurosci.1880-05.2006
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发表时间：
2006-02-22
影响因子：
5.3
通讯作者：
Yong, VW
中科院分区：
文献类型：
--
作者：
Larsen, PH;DaSilva, AG;Yong, VW
基质金属蛋白酶（MMP）参与神经系统内的几种活动。尽管异常升高的MMP的许多功能是不期望的，但是特定MMP成员的离散表达可以具有有益的作用。我们以前发现MMP-9在成年小鼠脊髓脱髓鞘病变周围局部表达促进髓鞘再生。在目前的研究中，我们已经解决了是否以及如何MMPs可能需要髓鞘形成在正常的个体发育。使用探针的多种基质金属蛋白酶和发展中的小鼠视神经，我们发现两个成员，MMP-9和-12，在髓鞘形成期间上调。这些MMPs参与髓鞘形成，因为与野生型小鼠相比，MMP-9和/或MMP-12缺失小鼠的胼胝体中的髓鞘形成从出生后第7天至第14天是缺乏的。与野生型相比，MMP缺失动物的髓鞘形成缺陷与较少的成熟少突胶质细胞相关，但与前体细胞数量相似。由于少突胶质细胞成熟的一个重要的生长因子是胰岛素样生长因子-1（IGF-1），我们讨论了这是否参与了MMP缺失小鼠的髓鞘形成缺陷。事实上，IGF-1的加入使MMP-12缺失小鼠培养物中发生的少突胶质细胞成熟的缺乏正常化。此外，我们确定，IGF结合蛋白6（IGFBP-6），隔离IGF-1，是MMP加工的底物。最后，我们发现MMP缺陷小鼠的IGFBP-6水平仍然很高。这些结果揭示了MMP-9和-12在发育髓鞘形成中可能通过调节IGF-1生物利用度的新功能。
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.