Ikonomov O C, Petrov T, Soden K, Shisheva A, Manji H K
Laboratory of Molecular Pathophysiology, Department of Psychiatry and Behavioral Neurosciences, Wayne State University, School of Medicine, 4237 Scott Hall, 540 E. Canfield, Detroit, MI 48201, USA.
Brain Res Dev Brain Res. 2000 Sep 30;123(1):13-24. doi: 10.1016/s0165-3806(00)00074-2.
Understanding the action of the mood stabilizer lithium is dependent on availability of experimental models where lithium treatment at clinically relevant concentrations induces marked phenotypic and genotypic changes. Here we report on such changes in the chicken embryo. Lithium chloride (0.6 mM), applied in ovo 60 h after incubation, markedly delayed the heart rate increase observed from ED2.5 to ED5, and induced the brain expression of a new chicken gene cETO from ED7 to ED15. At the same time the overall developmental dynamics and embryo survival, or the expression of chicken gephyrin were not significantly affected. Furthermore, lithium treatment (0.3 mM, 48 h after incubation) abolished the difference in neuronal number between ED12 ciliary ganglia developing in the presence or absence of postganglionic target muscles. We show that cETO is a close homologue of the human transcription factor MTG8/ETO; named after its location on chromosome 8, and participation in chromosomal translocation 8;21 in myeloid leukemia. The mRNA and protein levels of ETO and gephyrin had a parallel course in chicken brain development suggesting that the expression of both genes is regulated mainly at the level of gene transcription. However, the patterns of expression were markedly different. ETO peaked at ED7 and decreased five-fold at ED15. In contrast, gephyrin levels increased five-fold from ED7 to ED15. We propose that the induction of ETO expression, in concert with lithium-induced upregulation of other genes, such as PEBP2beta and bcl-2, is participating in the neuroprotective effect of chronic lithium treatment.
了解情绪稳定剂锂的作用，依赖于有实验模型可供使用，在这些模型中，临床相关浓度的锂治疗会引起显著的表型和基因型变化。在此，我们报告鸡胚中的此类变化。孵化60小时后在鸡胚中施用氯化锂（0.6 mM），显著延迟了从胚胎发育第2.5天（ED2.5）到第5天（ED5）观察到的心率增加，并在胚胎发育第7天（ED7）到第15天（ED15）诱导了新的鸡基因cETO在脑中的表达。同时，整体发育动态和胚胎存活率，或鸡gephyrin的表达均未受到显著影响。此外，锂治疗（0.3 mM，孵化后48小时）消除了在有或没有节后靶肌肉存在的情况下发育的胚胎发育第12天（ED12）睫状神经节之间神经元数量的差异。我们表明，cETO是人类转录因子MTG8/ETO的紧密同源物；因其位于8号染色体上，并参与髓系白血病中的8;21染色体易位而得名。ETO和gephyrin的mRNA和蛋白质水平在鸡脑发育过程中呈现平行变化，表明这两个基因的表达主要在基因转录水平受到调控。然而，它们的表达模式明显不同。ETO在ED7达到峰值，并在ED15下降了五倍。相比之下，gephyrin水平从ED7到ED15增加了五倍。我们提出，ETO表达的诱导，与锂诱导的其他基因如PEBP2β和bcl-2的上调协同作用，参与了慢性锂治疗的神经保护作用。
