FUNCTION AND REGULATION OF INTERCELLULAR COMMUNICATION

细胞间通讯的功能和调节

• 批准号: 6916435
• 负责人: DAVID L PAUL
• 金额: $ 41.53万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6916435
• 关键词: Schwann cells; Xenopus oocyte; astrocytes; cell cell interaction; disease /disorder model; gap junctions; gene targeting; genetically modified animals; hereditary motor and sensory neuropathy; immunocytochemistry; laboratory mouse; membrane channels; model design /development; myelination; oligodendroglia; protein localization; protein protein interaction; protein structure function; voltage /patch clamp

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.

描述（由申请人提供）： 以前，我们发现编码连接蛋白32（Cx 32）的基因突变导致了一种称为Charcot-Marie-Tooth病（CMTX）的脱髓鞘周围神经病变。与这一发现相一致，Schwann细胞含有Cx 32，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，少突胶质细胞也表达和调节Cx 32像髓鞘基因，但中央异常是罕见的CMTX患者。由于这种差异的一种解释是其他连接蛋白的冗余表达，我们在髓鞘形成胶质细胞中寻找连接蛋白。我们发现了两个新的连接蛋白，Cx 29和Cx47。所有这三种连接蛋白都可以在少突胶质细胞和雪旺细胞中找到。然而，Cx 29和Cx 32存在于脊髓少突胶质细胞的非重叠亚群中，虽然它们都存在于雪旺细胞中，但它们的亚细胞分布是惊人不同的。Cx 32或Cx47的单一敲除相对正常地形成髓鞘，并且没有功能缺陷。相比之下，双基因敲除会发生严重的中枢脱髓鞘，并在出生后第6周死亡。令人惊讶的是，这些动物仅显示外周髓鞘的细微异常。总之，我们的研究表明，连接蛋白是至关重要的中央和外周髓鞘，但不同的连接蛋白可能有不同的功能内髓鞘神经胶质细胞。我们建议使用免疫细胞化学，靶向基因消融和连接蛋白通道活性的功能分析相结合来定义连接蛋白在髓鞘形成中的独立和相互作用的作用。