Peter S. Klein, MD, PhD

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				Peter S. Klein, M.D., Ph.D. Asst Professor, Departments of Medicine and Cell and Developmental Biology Assistant Investigator, HHMI 364 CRB/6148 (215) 898-2179 Lab (215) 898-2319 email: pklein@mail.med.upenn.edu Click here for selected publications since Dr. Klein's arrival at Penn RESEARCH INTERESTS Wnt signaling in vertebrate development, neuronal signal transduction, neural crest development; mechanism of lithium action in behavior and development, chromatin structure, histone deacetylases (HDACs). RESEARCH TECHNIQUES Microinjection of oocytes and embryos, microsurgical manipulations of embryos, mouse behavioral assays, in-situ hybridization, standard biochemistry and molecular biology techniques, transgenic mice. RESEARCH SUMMARY This laboratory studies Wnt signaling and the mechanism of lithium action. We have found that lithium inhibits the enzyme glycogen synthase kinase-3 (GSK-3), which plays a role in several signal transduction pathways including the wnt pathway. We have identified novel GSK-3 inhibitors that mimic lithium action and are characterizing the effects of these inhibitors in mouse behavioral paradigms known to be affected by lithium. We have also generated transgenic mice expressing modulators of wnt signaling using inducible, neural specific promoters and are currently testing their effects in mouse behavioral paradigms. We have recently found that lithium and other GSK-3 inhibitors block generation of ß-amyloid peptides in cultured neurons and in a mouse model of Alzheimer's disease, and are continuing to study the role of GSK-3a in this regulation. This laboratory also studies Wnt signal transduction in Xenopus embryos. We have cloned several wnt receptors (frizzleds) and are currently analyzing their roles during embryogenesis. We are also using a biochemical approach to understand the mechanisms of Wnt transmembrane signaling. We have identified a novel PDZ domain containing protein that interacts strongly with the C terminus of frizzled-3 and inhibits its activity; this is the first protein to be identified that interacts directly with the cytoplasmic domain of frizzleds to modulate their function. We have also identified Xenopus Axin in a two hybrid screen with GSK-3ß as bait and are now studying the role of Axin in mediating the wnt-dependent inhibition of GSK-3ß. Additional, novel frizzled and GSK-3 interacting proteins expressed in early embryos have been identified, and these genes will be studied in the future. We are also actively studying the regulation of zygotic gene expression by Wnt signaling in the early embryo. KEY WORDS: lithium, GSK-3ß, wnt, frizzled, bipolar disorder, valproate, embryo development THE KLEIN LAB