Faculty Bibliography

Aripiprazole (APZ) is a novel antipsychotic agent which does not block dopamine (DA) receptors but is rather a partial DA agonist. Thus, it has been proposed that APZ may not induce tardive dyskinesia (TD), a disfiguring and sometimes disabling and irreversible side effect of neuroleptics. Our patient had Lewy body dementia (LBD) and developed severe worsening of parkinsonism over 1 month of APZ treatment. Within days of discontinuation of APZ dramatic orobuccal dyskinesias emerged. Treatment emergent worsening of parkinsonism improved but orobuccal dyskinesias persisted unchanged until his death 8 months later. Others have reported severe extrapyramidal reactions including neuroleptic malignant syndrome and TD with APZ. APZ has been suggested as a treatment for TD but treatment benefit may reflect 'masked' dyskinesia. We conclude that, despite an attractive in vitro profile and promising animal data, APZ can induce serious extrapyramidal side effects, including TD

In Drosophila, as in mammalian cells, the Raf serine/threonine kinase appears to act as a common transducer of signals from several different receptor tyrosine kinases. We describe a new role for Raf in Drosophila development, showing that Raf acts in the somatic follicle cells to specify the dorsoventral polarity of the egg. Targeted expression of activated Raf (Rafgof) within follicle cells is sufficient to dorsalize both the eggshell and the embryo, whereas reduced Raf activity ventralizes the eggshell. We show that Raf functions downstream of the EGF receptor to instruct the dorsal follicle cell fate. In this assay, human and Drosophila Rafgof are functionally similar, in that either can induce ventral follicle cells to assume a dorsal fate.

We have designed a system for targeted gene expression that allows the selective activation of any cloned gene in a wide variety of tissue- and cell-specific patterns. The gene encoding the yeast transcriptional activator GAL4 is inserted randomly into the Drosophila genome to drive GAL4 expression from one of a diverse array of genomic enhancers. It is then possible to introduce a gene containing GAL4 binding sites within its promoter, to activate it in those cells where GAL4 is expressed, and to observe the effect of this directed misexpression on development. We have used GAL4-directed transcription to expand the domain of embryonic expression of the homeobox protein even-skipped. We show that even-skipped represses wingless and transforms cells that would normally secrete naked cuticle into denticle secreting cells. The GAL4 system can thus be used to study regulatory interactions during embryonic development. In adults, targeted expression can be used to generate dominant phenotypes for use in genetic screens. We have directed expression of an activated form of the Dras2 protein, resulting in dominant eye and wing defects that can be used in screens to identify other members of the Dras2 signal transduction pathway.