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，我们表明编码Connexin32（CX32）的基因中的突变引起了一种被称为Charcot-Marie-Marie-tooth病（CMTX）的脱髓鞘周围神经病。与这一发现一致，Schwann细胞包含CX32并像髓磷脂相关基因一样调节其表达。 因此，在人周围神经系统中维持髓磷脂需要连接性的表达。然而，少突胶质细胞也像髓磷脂基因一样表达和调节CX32，而CMTX患者中心异常很少。由于这种差异的一种解释是其他连接素的冗余表达，因此我们在髓质神经胶质中搜索了连接蛋白。我们发现了两个新型的连接蛋白CX29和CX47。所有三个连接素都可以在少突胶质细胞和雪旺氏细胞中找到。然而，CX29和CX32存在于脊髓少突胶质细胞的非重叠子集中，虽然它们都存在于Schwann细胞中，但它们的亚细胞分布却大不相同。 CX32或CX47髓鞘的单个敲除相对正常，并且没有功能缺陷。相比之下，在产后的第六周，双重淘汰赛会形成严重的中央脱髓鞘和死亡。令人惊讶的是，这些动物仅在外周髓磷脂中显示出微妙的异常。总之，我们的研究表明，连接素对中央和周围髓鞘化至关重要，但是不同的连接蛋白可能在髓质神经胶质中具有不同的功能。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来定义连接素在髓鞘中的单独和相互作用的作用。