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Midbrain neurons synthesizing the neurotransmitter dopamine play a central role in the modulation of different brain functions and are associated with major neurological and psychiatric disorders. Despite the importance of these cells, the molecular mechanisms controlling their development are still poorly understood. The secreted glycoprotein Wnt1 is expressed in close vicinity to developing midbrain dopaminergic neurons. Here, we show that Wnt1 regulates the genetic network, including Otx2 and Nkx2-2, that is required for the establishment of the midbrain dopaminergic progenitor domain during embryonic development. In addition, Wnt1 is required for the terminal differentiation of midbrain dopaminergic neurons at later stages of embryogenesis. These results identify Wnt1 as a key molecule in the development of midbrain dopaminergic neurons in vivo. They also suggest the Wnt1-controlled signaling pathway as a promising target for new therapeutic strategies in the treatment of Parkinson's disease.

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Introduction Monoamine-based antidepressants inhibit neurotransmitter reuptake within short time. However, it commonly takes several weeks until clinical symptoms start to resolve-indicating the involvement of effects distant from reuptake inhibition. Objective To unravel other mechanisms involved in drug action, a "reverse" pharmacological approach was applied to determine antidepressant-induced alterations of hippocampal gene expression. Materials and methodsThe behavioral response to longterm paroxetine administration of male DBA/2Ola mice was assessed by the forced swim test (FST), the modified hole board (mHB), and the dark/light box. Hippocampi of test-naive mice were dissected, and changes in gene expression by paroxetine treatment were investigated by means of microarray technology. Results and discussion Robust effects of paroxetine on passive stress-coping behavior in the FST were observed. Furthermore, anxiolytic properties of long-term antidepressant treatment could be identified in DBA mice in both, the mHB and dark/light box. Analysis of microarray results revealed a list of 60 genes differentially regulated by chronic paroxetine treatment. Preproenkephalin 1 and inhibin beta-A showed the highest level of transcriptional change. Furthermore, a number of candidates involved in neuroplasticity/neurogenesis emerged (e.g., Bdnf, Gfap, Vim, Sox11, Egr1, Stat3). Seven selected candidates were confirmed by in situ hybridization. Additional immunofluorescence colocalization studies of GFAP and vimentin showed more positive cells to be detected in long-term paroxetine-treated DBA mice. Conclusion Candidate genes identified in the current study using a mouse strain validated for its responsiveness to long-term paroxetine treatment add, in our opinion, to unraveling the mechanism of action of paroxetine as a representative for SSRIs.

Foamy viruses (FVs) make use of a replication strategy which is unique among retroviruses and shows analogies to hepadnaviruses. The presence of an integrase (IN) and obligate provirus integration distinguish retroviruses from hepadnaviruses. To clarify whether a functional IN is required for FV replication, a mutant in the highly conserved DD35E motif of the active centre was analysed. This mutant was found to be able to express Gag and Pol protein precursors and cleavage products and to generate and deliver cDNA. However, this mutant was replication-deficient. The junctions of individual foamy proviruses with cellular DNA were sequenced. The findings suggest that FV integration is asymmetrical, because the proviruses started with what is believed to be the U3 end of the free linear DNA to generate the conventional TG dinucleotide, while apparently two nucleotides from the U5 end were cleaved to create the complementary CA dinucleotide. Alignment of known FV genome sequences indicated that this mechanism of integration is not restricted to the two FV isolates from which integrates were studied, but appears to be a common feature of this retrovirus subfamily. In conclusion, with respect to the necessity of a functionally active IN for virus replication FVs behave like other retroviruses ; their mechanism of integration, however, is probably unique.