The University of Arizona




UA Life Science Research - BioGate


Linda L. Restifo MD, PhD

Professor


Linda Restifo Contact Information

Address: Gould Simpson 423
1040 E. 4th Street
PO Box 210077
Tucson, AZ 85721-0077
Phone: (520) 621-9821
E-Mail: llr@neurobio.arizona.edu

Degrees
Department Affiliations
Program Affiliations
Research Areas

home Faculty Homepage

Research Interests

Genetics of brain development and neuronal plasticity; genetics of mental retardation

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.

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.

 Hundreds of human genes can mutate to a mental retardation (MR) phenotype, either in isolation or as part of a syndrome. We used bioinformatics methods to show that 75% of human MR genes have a candidate functional ortholog in Drosophila. To date, four of the Drosophila genes have been shown by others to have learning or memory phenotypes, and we predict that this will be true for many more of them. We showed that mutants of Drosophila fragile X mental retardation 1 (dfmr1) have defects in mushroom body development during metamorphosis. A major new initiative uses mushroom body cell culture methods to search for neuronal phenotypes of MR gene mutants in vitro. Our long-term goal is to use the Drosophila system as a stepping stone for discovery of drugs that will benefit human MR patients.

Selected Publications

Halladay AK, Amaral D, Aschner M, Bolivar VJ, Bowman A, DiCicco-Bloom E, Hyman SL, Keller F, Lein P, Pessah I, Restifo LL, and Threadgill DW. Jul 2009. Animal models of autism spectrum disorders: information for neurotoxicologists. Neurotoxicology, 30 (5):811-21

abstract Spokony RF, Restifo LL. Nov 2009. Broad Complex isoforms have unique distributions during central nervous system metamorphosis in Drosophila melanogaster. J Comp Neurol, 517:15-36

Narro ML, Yang F, Kraft R, Wenk C, Efrat A, Restifo LL. Mar 2007. NeuronMetrics: software for rapid semi-automated processing of cultured-neuron images. Brain Research, 1138:57-75

Spokony RF, Restifo, LL. Jul 2007. Anciently duplicated Broad Complex exons have distinct temporal functions during tissue morphogenesis. Development Genes and Evolution, 217:499-513


Update your profile