Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus
Conditional loss of Dicer disrupts cellular and tissue morphogenesis in the cortex and hippocampus
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DOI：
10.1523/jneurosci.4815-07.2008
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发表时间：
2008-04-01
影响因子：
5.3
通讯作者：
Ullian, Erik M.
中科院分区：
文献类型：
--
作者：
Davis, Tigwa H.;Cuellar, Trinna L.;Ullian, Erik M.
为了研究DICER和microRNAs在哺乳动物中枢神经系统中的作用，我们使用了DICER的第二个RNaseIII结构域有条件地漂浮的小鼠。用表达α-钙调蛋白激酶II Cre的小鼠在体内选择性地灭活兴奋性前脑神经元中的Dester，培育出条件性Dester小鼠。Dier的失活导致了一系列的表型，包括小头畸形，树突状分支精化减少，树突棘长度大幅增加，而脊椎密度没有伴随的变化。小头畸形可能是由于这些动物出生后早期的细胞凋亡增加了5.5倍，这是通过皮质中活跃的caspase-3和TUNEL(末端脱氧核苷酸转移酶介导的生物素化UTP缺口末端标记)染色确定的。原位杂交结果显示，小头畸形并不是由神经元迁移缺陷引起的，而是由于神经元移行缺陷所致。综上所述，这些结果说明了哺乳动物中枢神经系统中DICER和miRNAs的体内意义，并为先前的体外研究提供了额外的支持，这些研究表明，该途径的错误调节可能导致细胞数量和功能的严重异常，从而可能导致各种神经疾病。
To investigate the role of Dicer and microRNAs in the mammalian CNS, we used mice in which the second RNase III domain of Dicer was conditionally floxed. Conditional Dicer mice were bred with mice expressing an alpha-calmodulin kinase II Cre to selectively inactivate Dicer in excitatory forebrain neurons in vivo. Inactivation of Dicer results in an array of phenotypes including microcephaly, reduced dendritic branch elaboration, and large increases in dendritic spine length with no concomitant change in spine density. Microcephaly is likely caused by a 5.5-fold increase in early postnatal apoptosis in these animals as determined by active caspase-3 and TUNEL ( terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling) staining in the cortex. Loss of Dicer function had no measurable effect on cortical lamination as determined by in situ hybridization, suggesting that microcephaly is not caused by defects in neuronal migration. Together, these results illustrate the in vivo significance of Dicer and miRNAs in the mammalian CNS and provide additional support for previous in vitro studies indicating that misregulation of this pathway may result in gross abnormalities in cell number and function that may contribute to a variety of neurological disorders.