Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex
Tbr1 regulates regional and laminar identity of postmitotic neurons in developing neocortex
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DOI：
10.1073/pnas.1002285107
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发表时间：
2010-07-20
影响因子：
11.1
通讯作者：
Hevner, Robert F.
中科院分区：
文献类型：
--
作者：
Bedogni, Francesco;Hodge, Rebecca D.;Hevner, Robert F.
大脑皮层的区域和层次由遗传程序指定，遗传程序在祖细胞中启动，然后在有丝分裂后的神经元中实施。在这里，我们报告Tbr 1，有丝分裂后投射神经元中表达的转录因子，发挥积极和消极的控制区域（面积）和层状身份。Tbr 1基因敲除小鼠表现出额叶皮质和第6层分化的严重缺陷，如基因表达标记物如Bcl 6和Cdh 9的下调所示。相反，实现尾侧皮质和第5层身份的基因，如Bhlhb5和Fezf2，在Tbr 1突变体中上调。Tbr 1通过直接启动子结合和Auts2（一种与自闭症有关的额叶皮质基因）的激活来实现额叶身份。Tbr 1调节层身份的一部分，通过下游激活或维持Sox 5，一个重要的转录因子控制神经元迁移和离皮质轴突投射。与Sox 5突变体相似，Tbr 1突变体表现出向下丘脑和大脑脚的异位轴突投射。总之，我们的研究结果表明，Tbr 1协调调节有丝分裂后皮层神经元的区域和层状身份。
Areas and layers of the cerebral cortex are specified by genetic programs that are initiated in progenitor cells and then, implemented in postmitotic neurons. Here, we report that Tbr1, a transcription factor expressed in postmitotic projection neurons, exerts positive and negative control over both regional (areal) and laminar identity. Tbr1 null mice exhibited profound defects of frontal cortex and layer 6 differentiation, as indicated by down-regulation of gene-expression markers such as Bcl6 and Cdh9. Conversely, genes that implement caudal cortex and layer 5 identity, such as Bhlhb5 and Fezf2, were up-regulated in Tbr1 mutants. Tbr1 implements frontal identity in part by direct promoter binding and activation of Auts2, a frontal cortex gene implicated in autism. Tbr1 regulates laminar identity in part by downstream activation or maintenance of Sox5, an important transcription factor controlling neuronal migration and corticofugal axon projections. Similar to Sox5 mutants, Tbr1 mutants exhibit ectopic axon projections to the hypothalamus and cerebral peduncle. Together, our findings show that Tbr1 coordinately regulates regional and laminar identity of postmitotic cortical neurons.