Peripheral myelin protein 22 is in complex with α6β4 integrin, and its absence alters the Schwann cell basal lamina
Peripheral myelin protein 22 is in complex with α6β4 integrin, and its absence alters the Schwann cell basal lamina
复制标题
DOI：
10.1523/jneurosci.2618-05.2006
复制
发表时间：
2006-01-25
影响因子：
5.3
通讯作者：
Notterpek, L
中科院分区：
文献类型：
--
作者：
Amici, SA;Dunn, WA;Notterpek, L
外周髓磷脂蛋白22（PMP 22）是一种四环素膜糖蛋白，其错误表达与遗传性脱髓鞘神经病有关。髓鞘形成的雪旺细胞（SC）产生最高水平的PMP 22，但周围神经生物学中的蛋白质的功能尚未解决。为了研究PMP 22的潜在作用，我们通过用lacZ报告基因替换pmp 22的前两个编码外显子来设计新的敲除（-/-）小鼠系。PMP 22缺陷型小鼠在外周神经、软骨、肠和肺中显示出强烈的β-半乳糖苷酶反应性，而在表型上它们显示出脊髓神经病的特征。在没有PMP 22的情况下，周围神经的髓鞘形成延迟，并且许多轴突-SC轮廓显示松散的基底层，表明胶质细胞与细胞外基质的相互作用改变。在PMP 22缺陷小鼠的神经中，β 4整联蛋白（一种参与SC和基底层之间连接的分子）的水平严重降低。在髓鞘形成的早期阶段，PMP 22和β 4整联蛋白在细胞表面共表达，并且可以与层粘连蛋白和α 6整联蛋白一起免疫共沉淀。与此一致，在克隆A结肠癌细胞中，表位标记的PMP 22与β 4整联蛋白形成复合物。总之，这些数据表明，PMP 22是整合素/层粘连蛋白复合物中的结合伴侣，并参与介导SC与细胞外环境的相互作用。
Peripheral myelin protein 22 (PMP22) is a tetraspan membrane glycoprotein, the misexpression of which is associated with hereditary demyelinating neuropathies. Myelinating Schwann cells (SCs) produce the highest levels of PMP22, yet the function of the protein in peripheral nerve biology is unresolved. To investigate the potential roles of PMP22, we engineered a novel knock-out (-/-) mouse line by replacing the first two coding exons of pmp22 with the lacZ reporter. PMP22-deficient mice show strong beta-galactosidase reactivity in peripheral nerves, cartilage, intestines, and lungs, whereas phenotypically they display the characteristics of tomaculous neuropathy. In the absence of PMP22, myelination of peripheral nerves is delayed, and numerous axon-SC profiles show loose basal lamina, suggesting altered interactions of the glial cells with the extracellular matrix. The levels of beta 4 integrin, a molecule involved in the linkage between SCs and the basal lamina, are severely reduced in nerves of PMP22-deficient mice. During early stages of myelination, PMP22 and beta 4 integrin are coexpressed at the cell surface and can be coimmunoprecipitated together with laminin and alpha 6 integrin. In agreement, in clone A colonic carcinoma cells, epitope-tagged PMP22 forms a complex with beta 4 integrin. Together, these data indicate that PMP22 is a binding partner in the integrin/laminin complex and is involved in mediating the interaction of SCs with the extracellular environment.