Increased expression of tyrosine hydroxylase and anomalous neurites in catecholaminergic neurons of ATF‐2 null mice
Increased expression of tyrosine hydroxylase and anomalous neurites in catecholaminergic neurons of ATF‐2 null mice
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DOI：
10.1002/jnr.21510
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发表时间：
2008-02
影响因子：
4.2
通讯作者：
M. Kojima;Takahiro Suzuki;T. Maekawa;S. Ishii;C. Sumi-Ichinose;T. Nomura;H. Ichinose
中科院分区：
文献类型：
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作者：
M. Kojima;Takahiro Suzuki;T. Maekawa;S. Ishii;C. Sumi-Ichinose;T. Nomura;H. Ichinose
ATF‐2/CRE‐BP1最初被鉴定为大脑中丰富的cAMP - responsive element （CRE）结合蛋白。我们之前报道过ATF‐2的磷酸化增加了酪氨酸羟化酶（TH）的表达，这是儿茶酚胺生物合成的速率限制酶，直接作用于PC12D细胞中TH基因启动子区域的CRE （Suzuki et al. [2002] J. Biol.）。化学277:40768 - 40774)。为了研究ATF‐2在脑TH基因转录控制中的作用，我们研究了ATF‐2 - / -小鼠中TH的表达。我们发现，在ATF‐2缺陷胚胎的延髓和蓝斑中，TH的表达显著增加。TH的异位表达在中颌大细胞核中观察到，那里是血清素能神经细胞体的所在地。有趣的是，A10背侧神经元在ATF‐2 - / -小鼠胚胎中丢失。嗅球TH免疫反应性差异无统计学意义。数据显示，由于ATF‐2的缺失，TH的表达变化从脑的尾侧到吻侧逐渐下降。我们还发现ATF‐2缺失小鼠的儿茶酚胺能神经元中异常的神经突延伸，即树突树突增加和轴突缩短。这些数据表明，ATF‐2可能通过抑制因子样作用，在TH基因的正常表达和儿茶酚胺能神经元的神经突延伸中发挥关键作用。©2007 Wiley‐Liss, Inc。
ATF‐2/CRE‐BP1 was originally identified as a cAMP‐responsive element (CRE) binding protein abundant in the brain. We previously reported that phosphorylation of ATF‐2 increased the expression of tyrosine hydroxylase (TH), which is the rate‐limiting enzyme for catecholamine biosynthesis, directly acting on the CRE in the promoter region of the TH gene in PC12D cells (Suzuki et al. [2002] J. Biol. Chem. 277:40768–40774). To examine the role of ATF‐2 on transcriptional control of the TH gene in the brain, we investigated the TH expression in ATF‐2–/– mice. We found that TH expression was greatly increased in medulla oblongata and locus ceruleus of the ATF‐2‐deficient embryos. Ectopic expression of TH was observed in the raphe magnus nucleus, where serotonergic neural cell bodies are located. Interestingly, A10 dorsal neurons were lost in the embryos of ATF‐2–/– mice. There was no difference in the TH immunoreactivity in the olfactory bulb. The data showed that alteration in TH expression by absence of ATF‐2 gradually declined from caudal to rostral part of the brain. We also found anomalous neurite extension in catecholaminergic neurons of ATF‐2 null mice, i.e., increased dendritic arborization and shortened axons. These data suggest that ATF‐2 plays critical roles for proper expression of the TH gene and for neurite extension of catecholaminergic neurons, possibly through a repressor‐like action. © 2007 Wiley‐Liss, Inc.