Lithium treatment in ovo: effects on embryonic heart rate, natural death of ciliary ganglion neurons, and brain expression of a highly conserved chicken homolog of human MTG8/ETO.
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.
Ikonomov
O C
OC
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. oikonomo@med.wayne.edu
Petrov
T
T
Soden
K
K
Shisheva
A
A
Manji
H K
HK
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000166:cytology* / Q000187:drug effects; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D048429:Cell Size / Q000187:drug effects; D002645:Chickens; D003001:Cloning, Molecular; D005260:Female; D005726:Ganglia, Parasympathetic / Q000166:cytology* / Q000187:drug effects; D005838:Genotype; D006340:Heart Rate, Fetal / Q000187:drug effects*; D006801:Humans; D007294:Inositol / Q000378:metabolism; D008094:Lithium / Q000494:pharmacology*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D008969:Molecular Sequence Data; D010641:Phenotype; D011247:Pregnancy
D002352:Carrier Proteins; D008565:Membrane Proteins; C073441:gephyrin; D007294:Inositol; D008094:Lithium