Linda L. Restifo MD, PhD
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Genetics of brain development and neuronal plasticity; genetics of mental retardation In order to study genetic pathways that control brain morphogenesis and neuronal plasticity, we focus on the metamorphosis portion of development because the nervous system undergoes dramatic changes, including neuronal remodeling. These changes are under the control of a steroid hormone, 20-hydroxyecdysone (20E), whose receptor subunits are members of the nuclear receptor superfamily. At the cellular level, steroid hormone-induced changes in neuronal structure and function are very similar in mammals and insects. Many of our studies deal with a fascinating brain region, the mushroom bodies, which are remodeled during metamorphosis and which mediate complex adult behaviors, including some forms of learning and memory. We used dissociated cell culture methods to demonstrate that 20E promotes neurite outgrowth of mushroom body neurons harvested early in the metamorphic interval. We also found a number of neuronal morphology phenotypes in vitro, which suggested that cell culture could provide a sensitive assay system for identifying neuronal defects (see below). We determined that Broad Complex transcription factors play a pivotal role in mediating 20E-regulated nervous system metamorphosis. This family of BTB-zinc-finger proteins (BRC-Z1 through -Z4) is generated by alternative splicing of transcripts from a large gene directly induced by 20E in the CNS and other tissues. Transgenic-rescue and spatial expression studies support a model of BRC function in coordinating cell-cell interactions that underlie central nervous system morphogenetic movements.
My overarching interest is in the genetics of brain development, ranging from the control of large-scale morphogenetic movements to the remodeling of individual neurons. We use the fruit fly model system, Drosophila melanogaster, in part because of its phylogenetic similarities to mammals. In particular, we are using fruit flies to understand human developmental brain disorders, such as mental retardation and autism, and as a drug-discovery tool. Our methods include genetic manipulations, primary neuron cell culture, immunostaining and confocal microscopy, expression profiling (with Affymetrix microarrays), bioinformatics, and software development for neuron-image analysis.