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Peter S. Klein, M.D., Ph.D. Medline
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Lithium action and wnt signaling: Lithium remains the first line of therapy in the treatment of bipolar disorder, potently stimulates granulopoiesis in mammals, activates glycogen synthesis, and has profound effects on the development of diverse organisms. However, the mechanism of lithium action in these diverse settings is still not clear. We have found that lithium, at therapeutic concentrations, directly inhibits the enzyme glycogen synthase kinase-3ß (GSK-3ß), a critical regulator of several signal transduction pathways including the wnt and insulin pathways. We have also found that lithium inhibits GSK-3ß within neuronal cells and are now testing whether this inhibition can explain the behavioral effects of lithium in mice. In addition, we identified Xenopus axin as a GSK-3ß interacting gene and found that it is highly expressed in a restricted domain in the anterior midbrain of the developing CNS. More recently, we have identified a novel, alternative inhibitor of GSK-3ß, a short peptide derived from Xenopus axin, that mimics the developmental and transcriptional effects of lithium, leading to strong activation of the wnt pathway. This inhibitory peptide is currently being used to test whether the effect of litihum in other settings, such as mouse behavior and granulopoiesis, can be attributed to inhibition of GSK-3. We are also examining the effect of valproic acid (VPA), another therapy for bipolar disorder, on hematopoiesis. We have found that VPA inhibits proliferation and induces differeniation markers in hematopoietic stem cells and in cell lines derived from acute myelocytic leukemias. Since we have also found that VPA is a potent inhibitor of histone deacetylase, we are currently examining whether this explains the effect of VPA on hematopoietic cells. Wnt signal transduction in early development: We have identified a family of four wnt receptors (frizzleds) expressed in early Xenopus embryos. Frizzled-8 is highly expressed in the Spemann organizer of the Xenopus gastrula and its function is required for oriented cell movements during gastrulation. Our work on frizzled-8 was the first to define a specific function for a vertebrate frizzled gene. Subsequently, we have examined the specificity of wnt-frizzled interactions (there are 20 wnts and at least 15 frizzleds/receptors) using five frizzleds and eight wnts; this work led to the identification of specific interactions between wnt-1 and frizzled-3 and showed that frizzled 3 is required for the formation of neural crest in Xenopus. Furthermore, we have identified a novel protein (named kermit) that interacts with the cytoplasmic domain of frizzleds. We have found that kermit binding is specific for frizzled-3 and that kermit is required for frizzled-3 signaling in the induction of neural crest. This represents the first gene to be identified that 1) interacts with the cytoplasmic domain of frizzleds and 2) transduces wnt/frizzled signals. Recently, we identified a second kermit-like gene that specifically interacts with frizzled-8 but not frizzled-3, suggesting the existence of a family of kermit-related proteins associated with each of the various frizzleds. References Phiel, C.J., Zhang, F., Huang, E.Y., Gunther, M., Arzoumanian, A., Lazar, M.A., and Klein P.S. Histone Deacetylase is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen. J. Biol. Chem. 276:36734-36741, 2001. Kofron, M., Klein, P.S., Zhang, F., Houston, D.W., Schaible, K., Wylie, C., and Heasman, J. The Role of Maternal Axin In Patterning the Xenopus Embryo. Developmental Biology 237:183-201, 2001. Deardorff, M.A., Tan, C., Saint-Jeannet, J-P., and Klein, P.S. A Role for Frizzled-3 in Neural Crest Development. Development 128:3655-3663. Tan, T., Deardorff, M.A., Saint-Jeannet, J-P., and Klein, P.S. Kermit, a Frizzled Interacting Protein, Regulates Frizzled-3 Dependent Neural Crest Development. Development 128: 3665-3674. |
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