A novel locus on proximal chromosome 18 associated with agenesis of the corpus callosum in mice
A novel locus on proximal chromosome 18 associated with agenesis of the corpus callosum in mice
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DOI：
10.1007/s00335-010-9292-4
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发表时间：
2010-12-01
期刊：
影响因子：
2.5
通讯作者：
Yagami, Ken-ichi
中科院分区：
文献类型：
--
作者：
Mizuno, Seiya;Mizobuchi, Atsushi;Yagami, Ken-ichi
胼胝体发育是一种先天性脑结构异常。我们已经产生了转基因小鼠表达的逆转录四环素控制的反式激活因子（rtTA）和转录沉默（tTS）无处不在。虽然转基因产物不影响小鼠脑的发育，但其中一个创始品系TAS显示ACC，表明内源基因的转基因破坏。为了确定ACC的致病基因及其在ACC中的作用，我们对TAS小鼠的大脑进行了病理学研究，并对外源基因进行了染色体定位。62%的杂合子TAS小鼠显示ACC伴随Probst束的形成，如在人类中所见。在纯合子TAS小鼠中观察到ACC完全缺失。此外，纯合子TAS胎儿显示ACC是一种先天性异常。此外，胼胝体的轴突不排斥的中线神经胶质结构在TAS小鼠。这些发现表明ACC的致病基因参与了胼胝体发育的关键步骤。进行多次FISH分析以确定转基因插入的位点。在单色FISH分析中，在18号染色体的A/B区检测到rtTA和tTS，表明转基因的共整合。在双色FISH分析中，在18号染色体上9.3至16.9 Mb的区域中观察到tTS信号。TAS小鼠可作为一个有用的模型，以确定一个新的基因调控胼胝体发育和获得新的见解ACC的分子遗传学。
Agenesis of the corpus callosum (ACC) is a congenital abnormality of the brain structure. We have produced transgenic mice expressing both reverse tetracycline-controlled transactivator (rtTA) and transcriptional silencer (tTS) ubiquitously. Although the transgene products do not affect development of the mouse brain, one of the founder lines, TAS, showed ACC, suggesting transgenic disruption of endogenous gene(s). To identify the causative gene and its role in ACC, we performed pathological investigations of the brain and chromosomal mapping of foreign genes in TAS mice. Sixty-two percent of the heterozygous TAS mice showed ACC accompanied with formation of Probst bundles, as seen in human. Complete penetrance of ACC was observed in homozygous TAS mice. Furthermore, homozygous TAS fetuses revealed that ACC is a congenital anomaly. Moreover, axons of the corpus callosum were not repelled by the midline glial structures in TAS mice. These findings suggested that the causative gene for ACC is involved in critical steps in corpus callosum development. Multiple FISH analyses were performed to determine the site of transgene insertion. On 1-color FISH analyses, rtTA and tTS were detected on the A/B region of chromosome 18, suggesting cointegration of the transgenes. On 2-color FISH analyses, tTS signal was observed in a region from 9.3 to 16.9 Mb on chromosome 18. The TAS mice may serve as a useful model to identify a novel gene regulating corpus callosum development and to gain a new insight into molecular genetics of ACC.