How do Cx32 and Cx47 mutants cause CNS demyelination?

描述（由申请人提供）： CNS髓鞘形成依赖于连接蛋白32（Cx 32）和Cx47的适当功能，它们是由少突胶质细胞表达的间隙连接蛋白。编码这些连接蛋白的基因GJB 1/Cx 32和GJA 12/Cx47的缺陷导致CNS白色物质道疾病，分别包括X连锁夏科-马里-图思病和佩-梅二氏样病。在小鼠中GJB 1/Cx 32和GJA 12/Cx47基因的缺失导致严重的髓鞘形成障碍表型和6周龄时的死亡，这在单独缺失任一基因时都不会发生，表明这些蛋白质具有重叠的功能。解剖学和功能研究表明，缝隙连接耦合星形胶质细胞和少突胶质细胞，Cx 32和Cx47可能包括这些缝隙连接通道的少突胶质细胞部分。我们提出，编码Cx 32和Cx47的基因突变破坏了星形胶质细胞和少突胶质细胞之间的偶联。这项资助的目的是研究突变型Cx 32和突变型Cx47在与由相同细胞和并置细胞表达的连接蛋白相互作用的背景下的特性。这项工作应阐明耦合星形胶质细胞和少突胶质细胞的间隙连接通道的分子组成。

DESCRIPTION (provided by applicant): CNS myelination depends on the proper function of connexin32 (Cx32) and Cx47, which are gap junction proteins expressed by oligodendrocytes. Defects in the genes that encode these connexins, GJB1/Cx32 and GJA12/Cx47, cause CNS white matter tract disorders, including X-linked Charcot-Marie-Tooth Disease and Pelizaeus-Merzbacher-like Disease, respectively. Deletion of both GJB1/Cx32 and GJA12/Cx47 genes in mice results in a severe dysmyelinating phenotype and death by six weeks of age that does not occur with deletion of either gene alone, suggesting that these proteins serve overlapping functions. Anatomical and functional studies demonstrate that gap junctions couple astrocytes and oligodendrocytes, and Cx32 and Cx47 likely comprise the oligodendrocyte portion of these gap junction channels. We propose that mutations in the genes that encode Cx32 and Cx47 disrupt coupling between astrocytes and oligodendrocytes. The goal of this grant is to investigate the properties of mutant Cx32 and mutant Cx47 in the context of interactions with connexins expressed by the same cells and by apposing cells. This work should elucidate the molecular composition of gap junction channels that couple astrocytes and oligodendrocytes.