Description of Research Expertise

Research Interests
Early vertebrate development, Wnt signal transduction, neuropharmacology of lithium action

Key words: Wnt, embryo, signal transduction, developmental biology, lithium, chromatin, Xenopus, GSK-3.

Description of Research
This lab is studying wnt signal transduction during early embryogenesis and the mechanism of lithium action in neuropsychiatric disorders. Areas of current research include the role of wnt signaling components, including wnt receptors (e.g. frizzleds) and intracellular components (e.g. axin), in early embryogenesis and the mechanisms of wnt/frizzled signal transduction. Approaches include microinjection of mRNAs, RNA interference, and transgenics. The lab has recently shown that wnt signaling regulates transcription in the early embryo, prior to the midblastula transition (MBT). It was previously widely believed that transcription of the embryonic genome in many organisms is completely silenced during these early stages. We are therefore examining the mechanisms by which specific wnt responsive genes escape transcription repression prior to MBT and are identifying targets of preMBT transcription. This work includes examination of temporal changes in chromatin structure and micorarray analyses to identify genes regulated during preMBT stages.

This laboratory has found that lithium inhibits the protein kinase GSK-3, a negative regulator of wnt signaling. Current work addresses the role of GSK-3 in mediating the neuropsychiatric effects of lithium in bipolar disorder and in Alzheimer’s disease. We are examining the biochemical, molecular, and behavioral effects of this GSK-3 inhibitor in transgenic mice and are comparing it to the behavioral and molecular phenotypes of GSK-3ß knock-out mice as well as lithium treated mice. In addition, we have found that valproic acid, also used to treat bipolar disorder, is a histone deacetylase inhibitor, and we are currently examining the pharmacology of this inhibition as well as a potential role for this HDAC inhibitor in cancer chemotherapy. Finally, we have found that lithium and other GSK-3 inhibitors block processing of the amyloid precursor protein (APP), and so inhibit formation of the ß-amyloid peptides associated with Alzheimer’s disease. Future work will involve examination of conditional GSK-3 knock out mice.

Rotation Projects for 2006-2007
1. Regulation of Wnt signaling through the Axin-APC-GSK-3 complex in dorsal ventral patterning.

2. Wnt and lithium activated gene expression in mouse brain.

3. PreMBT regulation of dorsal-ventral patterning and Wnt signaling in Xenopus embryos.

4. Use of microarray and differential screening to identify novel preMBT genes; characterization of function of genes expressed before MBT.

5. Targeting GSK-3 in models of Alzheimer's disease; regulation of GSK-3 activity in mouse brain.

6. Reverse two-hybrid analysis of protein-protein interactions in the Wnt pathway.

7. Conditional protein-protein interactions in Xenopus embryos.

Lab personnel:
Robbie Fagan, research technician
Shelby Blythe, graduate student
Rishita Shah, graduate
Tim O'Brien, postdoctoral fellow
Jian Huang, postdoctoral fellow
Jennifer Skirkanich, graduate
Mike O'Donnell, research technician
Arpine Arzoumanian, research technician