Connexin32 mutations cause loss of function in Schwann cells and oligodendrocytes leading to PNS and CNS myelination defects.
Connexin32 mutations cause loss of function in Schwann cells and oligodendrocytes leading to PNS and CNS myelination defects.
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DOI：
10.1523/jneurosci.0325-09.2009
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发表时间：
2009-04-15
期刊：
影响因子：
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通讯作者：
Kleopa KA
中科院分区：
文献类型：
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作者：
Sargiannidou I;Vavlitou N;Aristodemou S;Hadjisavvas A;Kyriacou K;Scherer SS;Kleopa KA
间隙连接蛋白Cx32由髓鞘雪旺细胞和少突胶质细胞表达，在X连锁Charcot-Marie-Tooth病(CMT1X)中发生突变。除了脱髓鞘周围神经病，一些Cx32突变还与一过性或慢性CNS表型有关。为了研究这些表型的分子基础，我们建立了由小鼠CNP启动子驱动的表达T55I或R75W突变和IRES-EGFP的转基因小鼠。转基因在中枢神经系统的少突胶质细胞和雪旺细胞中均有表达。T55I和R75W突变体均定位于核周细胞质，不形成GJ斑块，也不改变另外两种少突胶质细胞GJ蛋白Cx47和Cx29的表达或定位，也不改变Cx29在雪旺细胞中的表达。在野生型背景下，内源mCx32的表达不受T55I突变体的影响，但受到R75W的部分抑制。具有R75W突变的转基因小鼠和所有背景为Gjb1缺失的突变小鼠发展为进行性脱髓鞘周围神经病，并伴有中枢神经系统髓鞘缺陷。这些发现表明，Cx32突变导致有髓细胞功能丧失，而对其他GJ蛋白没有反式显性影响。仅在中枢神经系统中Cx32功能的丧失就会导致髓鞘缺陷。
The gap junction (GJ) protein connexin32 (Cx32) is expressed by myelinating Schwann cells and oligodendrocytes and is mutated in X-linked Charcot-Marie-Tooth disease (CMT1X). In addition to a demyelinating peripheral neuropathy, some Cx32 mutants are associated with transient or chronic CNS phenotypes. To investigate the molecular basis of these phenotypes, we generated transgenic mice expressing the T55I or the R75W mutation and an IRES-EGFP, driven by the mouse Cnp promoter. The transgene was expressed in oligodendrocytes throughout the CNS and in Schwann cells. Both the T55I and the R75W mutants were localized in the perinuclear cytoplasm, did not form GJ plaques, and did not alter the expression or localization of two other oligodendrocytic GJ proteins, Cx47 and Cx29, or the expression of Cx29 in Schwann cells. On wild type background, the expression of endogenous mCx32 was unaffected by the T55I mutant, but was partly impaired by R75W. Transgenic mice with the R75W mutation and all mutant animals with Gjb1-null background developed a progressive demyelinating peripheral neuropathy along with CNS myelination defects. These findings suggest that Cx32 mutations result in loss of function in myelinated cells without trans-dominant effects on other GJ proteins. Loss of Cx32 function alone in the CNS causes myelination defects.