 |
LAWRENCE T. REITER, Ph.D.
Address
Education
Research InterestsMy laboratory utilizes the powerful genetic model organism Drosophila melanogaster (fruit flies) to investigate the functions of genes involved in human neurological disease. Our main focus is the study of genes related to autism and autism spectrum disorders. Autism spectrum disorders include the severely debilitating fragile X, Rett (RTT) and Angelman syndromes (AS). These disorders appear to be interrelated at the molecular level one of the goals of our laboratory is to identify genes and proteins regulated by one or more of the proteins that, when mutated, cause fragile X, RTT or AS. In addition, approximately 3 % of all inherited autism cases may result from maternally inherited duplications of the region containing the gene that causes AS, UBE3A. Mutations in the protein targets of the ubiquitin ligase UBE3A, the transcriptional regulator MECP2 or the transcripts regulated by the fragile X gene FMRP, may account for a significant percentage of inherited autism cases. In our laboratory we utilize Drosophila specific genetic techniques that allow us to generate artificially high levels of normal and mutant fly ube3a proteins in fly heads. Wild type, dominant negative and epitope tagged forms of ube3a are over-expressed in the brains of flies using the GAL4/UAS system in order to increase or decrease the levels of ube3a protein targets. We then identify these targets by 2 D gel electrophoresis and mass spectrometry (proteomics). Potential targets are then validated though genetic suppressor/enhancer screens, looking for changes in fly neurons after deletion of these target genes, immunoprecipitation binding assays in cell culture and immunohistochemistry in the brains of the appropriate mouse models. Another aspect of our work is related to describing various quantifiable behavior phenotypes in Ube3a, Fmr1 and Mecp2 deficient mice. Specifically, we are interested in abnormal social behavior (a measure of autistic behavior in mice) as well as abnormal fluid licking behavior (a natural behavior which reflects cerebellar function). These experiments have already shown that Ube3a deficient animals have measurable deficits in fluid licking that are directly related to the decrease in Ube3a levels in the brain (Heck DH, Zhao Y, Roy S, LeDoux MS, Reiter LT. 2008. Analysis of cerebellar function in Ube3a-deficient mice reveals novel genotype-specific behaviors. Hum Mol Genet. 17(14):2181-9). An important additional area of our research is the in depth phenotypic and molecular analysis of individuals with interstitial duplication 15q autism. Since 2007 we have been collecting a variety of language, neuropsychiatric, neurological and gene expression data from subjects with interstitial 15q chromosomal duplications. We hope that our basic research into the functional targets of UBE3A will lead to a better understanding of the phenotypes in this particular autism population where the UBE3A gene is duplicated, and presumably expressed at higher levels than in unaffected individuals. For more information on our clinical study see http://www.idic15.org/res_cur_reiter.php. LinksRecent Publications
|