FUNCTION AND REGULATION OF INTERCELLULAR COMMUNICATION

描述(申请人提供)：之前，我们发现编码连接蛋白32(Cx32)的基因突变会导致一种名为夏科-玛丽-图思病(CMTX)的脱髓鞘周围神经病。与这一发现一致的是，雪旺细胞含有Cx32，并像髓鞘相关基因一样调节其表达。因此，人类周围神经系统中髓鞘的维持需要连接蛋白的表达。然而，少突胶质细胞也像髓鞘基因一样表达和调节Cx32，然而在CMTX患者中中枢异常很少见。由于这种差异的一种解释是其他连接蛋白的过度表达，我们在髓鞘胶质细胞中寻找连接蛋白。我们发现了两个新的连接蛋白，Cx29和Cx47。这三种连接蛋白均存在于少突胶质细胞和雪旺细胞中。然而，Cx29和Cx32存在于不重叠的脊髓少突胶质细胞亚群中，虽然它们都存在于雪旺细胞中，但它们的亚细胞分布截然不同。Cx32或Cx47的单个敲除的髓鞘形成相对正常，没有功能缺陷。相反，双基因敲除会发展成严重的中枢脱髓鞘，并在出生后6周死亡。令人惊讶的是，这些动物的外周髓鞘只显示出轻微的异常。总之，我们的研究表明，连接蛋白对中枢和外周髓鞘形成都是至关重要的，但不同的连接蛋白在髓鞘胶质细胞中可能具有不同的功能。我们建议结合免疫细胞化学、靶向基因去除和连接蛋白通道活性的功能分析来确定连接蛋白在髓鞘形成中的独立和相互作用的作用。

DESCRIPTION (provided by applicant): Previously, we showed that mutations in the gene encoding connexin32 (Cx32) caused a demyelinating peripheral neuropathy called Charcot-Marie-Tooth disease (CMTX). Consistent with this finding, Schwann cells contain Cx32 and regulate its expression like a myelin-related gene. Thus, maintenance of myelin in the human peripheral nervous system requires connexin expression. However, oligodendrocytes also express and regulate Cx32 like a myelin gene and yet central abnormalities are rare in CMTX patients. Since one explanation for this discrepancy would be redundant expression of other connexins, we searched for connexins in myelinating glia. We found two novel connexins, Cx29 and Cx47. All three connexins can be found in oligodendrocytes and Schwann cells. Cx29 and Cx32, however, are present in non-overlapping subsets of spinal cord oligodendrocytes and,while they are both present in Schwann cells, their subcellular distributions are strikingly different. Single knockouts of either Cx32 or Cx47 myelinate relatively normally and have no functional deficits. In contrast, double knockouts develop severe central demyelination and die during the 6th postnatal week of life. Surprisingly, these animals display only subtle abnormalities in peripheral myelin. Together, our studies suggest that connexins are critical for both central and peripheral myelination but that different connexins may have different functions within myelinating glia. We propose to define the separate and interacting roles of connexins in myelination using a combination of immunocytochemistry, targeted gene ablation and functional analysis of connexin channel activity.