The rhythm and blues of gene expression in the rodent pineal gland.

In all vertebrates, melatonin is rhythmically synthesized in the pineal gland and functions as a hormonal message, encoding for the duration of night. In rodents, the nocturnal rise and fall of the arylalkylamine N-ace-tyltransferase (AA-NAT) activity controls the rhythmic synthesis of melatonin. This rhythm is centered around the transcriptional regulation of the AA-NAT by two norepinephrine-inducible transcription factors, the activator CREB (Ca2+/cAMP-response element binding protein) and the inhibitor ICER (inducible cAMP early repressor). CREB is activated by phosphorylation, which is one of the fastest responses in pinealocytes upon adrenergic stimulation, occurring within minutes. ICER in turn accumulates only after several hours, a time gap resulting from the required de novo protein synthesis upon adrenergic stimulation. However, these molecular components of neuroendocrine signaling in the rodent pineal gland are supplemented by the impact of a variety of neurotransmitters and neuromodulators, and by translational and post-translational mechanisms. By molecular crosstalk, those different inputs on pinealocytes seem to fine-tune the shape of the melatonin signal, by interacting at various levels with the NE/cAMP/pCREB/ICER pathway. In addition, these alternate signaling routes may be important in acute "emergency" situations. Together, concerted signaling events in the rodent pineal gland help to generate a stable and reliable hormonal message of darkness for the body, that, however, can be altered rapidly upon sudden and unexpected "error" signals.

Estradiol stimulates GDNF expression in developing hypothalamic neurons.

Estrogens stimulate the differentiation of neurons and neural networks in the CNS. The concordance of the cellular responses of estrogens and growth factors suggests that both factors may interact on the cellular level to ensure their developmental role. We have put forward this hypothesis and analyzed the effect of estrogens on the expression of glial cell line-derived neutrotrophic factor (GDNF) in developing hypothalamic cells. Using Western blotting and competitive RTPCR, we have demonstrated that 17beta-estradiol (E2) increases the expression of GDNF in hypothalamic cell cultures. E2-induced GDNF expression was seen in neurons but not astrocytes. GDNF induction by E2 appeared to be transmitted through nonclassical estrogen action, since the application of the nuclear estrogen receptor antagonists ICI 182, 780 did not abolish this effect. Only inhibitors of intracellular Ca(2+) and cAMP/protein kinase A signaling were effective in preventing E2 effects. We conclude that E2 is capable of influencing GDNF expression in the developing hypothalamus. Thus, it is conceivable that developmental E2 effects in the hypothalamus are partially mediated through the regulation of other important developmental signals such as growth factors.