Wnt signaling is important for major developmental patterning events in the brain. Examples include early specification of the midbrain/hindbrain boundary, cell proliferation and differentiation in the hippocampus and cerebellum, and later maturation events including synaptogenesis and dendritic arborization. These contributions to the regulation of brain development may in themselves be important for understanding the etiology of psychiatric disorders, many of which are likely to have a neurodevelopmental component. But the role of Wnt signaling in behavioral illness may go beyond development as traditionally defined. Mice engineered to have a genetic defect in the Wnt pathway component Dvl-1 undergo grossly normal brain development but nevertheless display behavioral deficits reminiscent of schizophrenia. Schizophrenic humans have been found to have decreased levels of two other Wnt signaling pathway components, Gsk-3 and ß-catenin, in their cerebral cortices. Gsk-3 is a kinase whose activity is altered by both lithium and valproate, two widely-used psychiatric drugs. ß-catenin biochemically interacts with the Presenilin proteins implicated in familial Alzheimer's Disease. These observations suggest that Wnt signaling may be involved in an array of neuropsychiatric disorders occurring at all stages of the human life-cycle.

The major experimental paradigm in our lab is the neurodevelopmental and behavioral characterization of mice engineered to have defects in Wnt pathway component genes. A current major thrust is the characterization of mice with defects in an intracellular modulator of Wnt signaling, Dact (Dpr/Frd). This work is complemented by standard assays of Wnt signaling based on mammalian tissue culture. Other projects include the identification of novel gene products that interact with Wnt pathway components in the mammalian brain, exploration of the functional significance of these interactions, and an analysis of the differential expression of Wnt gene products in the adult brain. Our hope is that these investigations will ultimately yield insights into the molecular basis for human behavior, neurobehavioral illness, and its treatment.