A role for connexin43 during neurodevelopment
A role for connexin43 during neurodevelopment
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DOI：
10.1002/glia.20484
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发表时间：
2007-05-01
期刊：
影响因子：
6.2
通讯作者：
McCarthy, Ken D.
中科院分区：
文献类型：
--
作者：
Wiencken-Barger, Amy E.;Djukic, Biljana;McCarthy, Ken D.
缝隙连接蛋白43（Cx43）是有丝分裂前放射状胶质细胞和成熟星形胶质细胞中表达的主要缝隙连接蛋白。它被认为在大脑发育和生理学的许多方面发挥作用，包括细胞间通讯、神经活性物质的释放以及神经和胶质细胞的增殖和迁移。为了研究Cx43在脑生理学中的作用，我们产生了一个条件性敲除（cKO）小鼠表达Cre重组酶驱动的人GFAP启动子和一个flox 43基因。从表达GFAP的细胞中去除Cx43会影响小鼠的行为和几种脑结构的发育;然而，表型的严重程度取决于小鼠的背景。一种小鼠亚系，下文称为Shuffler，表现出皮质、海马和小脑的细胞紊乱，伴有共济失调和运动缺陷。Shuffler小脑受影响最大，并显示胶质细胞和神经元的分布和分层改变，提示细胞迁移缺陷。在出生后第二天（P2）的所有Shuffler小鼠中，海马、皮质和小脑都较小。脑皮质的脑室和脑室下区的结构紊乱也很明显。鉴于这些是早期祖细胞增殖的位点，我们怀疑神经祖细胞的产生和迁移可能会改变。总之，Shuffler/Cx43 cKO小鼠的神经发育是异常的，观察到的细胞表型可以解释在这些动物以及携带Cx43突变的人类中观察到的行为障碍。(c)2007 Wiley-Liss，Inc.
Connexin43 (Cx43) is the predominant gap junction protein expressed in premitotic radial glial cells and mature astrocytes. It is thought to play a role in many aspects of brain development and physiology, including intercellular communication, the release of neuroactive substances, and neural and glial proliferation and migration. To investigate the role of Cx43 in brain physiology, we generated a conditional knockout (cKO) mouse expressing Cre recombinase driven by the human GFAP promoter and a floxed Cx43 gene. The removal of Cx43 from GFAP-expressing cells affects the behavior of the mice and the development of several brain structures; however, the severity of the phenotype varies depending on the mouse background. One mouse subline, hereafter termed Shuffler, exhibits cellular disorganization of the cortex, hippocampus, and cerebellum, accompanied by ataxia and motor deficits. The Shuffler cerebellum is most affected and displays altered distribution and lamination of glia and neurons suggestive of cell migration defects. In all Shuffler mice by postnatal day two (P2), the hippocampus, cortex, and cerebellum are smaller. Disorganization of the ventricular and subventricular zone of the cortex is also evident. Given that these are sites of early progenitor cell proliferation, we suspect production and migration of neural progenitors may be altered. In conclusion, neurodevelopment of Shuffler/Cx43 cKO mice is abnormal, and the observed cellular phenotype may explain behavioral disturbances seen in these animals as well as in humans carrying Cx43 mutations. (c) 2007 Wiley-Liss, Inc.