Benjamin Cheyette, M.D., Ph.D.
Assistant Professor of Psychiatry



Contact Information:
bc@lppi.ucsf.edu
Tel: (415) 476-7826
Fax: (415) 476-7884
Lab: (415) 476-7899

Rock Hall, UCSF
1540 4th Street, Room 284A,
Box 2611
San Francisco, CA 94158-2611

Links:
Lab website

Tetrad
Neuroscience
Biomedical Sciences
Wheeler Center for the Neurobiology of Addiction

Publications

Wnt Signaling in Development and Function of the Mammalian Brain

Intercellular communication is critical for the development and function of the tissues that make up multicellular organisms. Our laboratory is interested in the role of non-neurotransmitter-mediated intercellular communication in the development and function of the mammalian brain. Our focus is on one type of intercellular communication known as Wnt signaling. Wnts are an ancient family of secreted glycoproteins that are conserved across animal species. Transmembrane Wnt receptors transmit signals from the extracellular space to the cytoplasm and nucleus through several increasingly well-characterized protein cascades. Wnt signaling takes part in developmental decisions across tissue types, and its misregulation has been implicated in a wide variety of human diseases.

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 reportedly undergo 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 beta-catenin, in their cerebral cortices. Gsk-3 is a kinase whose activity is altered by both lithium and valproate, two widely-used psychiatric drugs. Beta-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 main 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 a recentlydiscovered vertebrate inhibitor of Wnt signaling, Dpr. This work is complemented by assays of Wnt signaling based on mammalian tissue culture. Other projects include the identification of novel gene products that interact with Wnt pathway components, coupled with an exploration of the functional significance of these molecules and their interactions in the developing and mature brain. Our hope is that these investigations will ultimately yield insights into the molecular basis for human behavior, neurobehavioral illness, and its treatment.

Selected Publications:
Ebens, A.J., Garren H., Cheyette, B.N.R., and Zipursky, S.L. (1993). The Drosophila anachronism locus: a glycoprotein secreted by glia inhibits neuroblast proliferation. Cell 74, 15-27.

Cheyette, B.N.R., Green, P.J., Martin, K., Garren H., Hartenstein, V., and Zipursky, S.L. (1994). The Drosophila sine oculis locus encodes a homeodomain-containing protein required for the development of the entire visual system. Neuron 12, 977-996.

Oliver, G., Wehr, R., Jenkins, N.A., Copeland, N.G., Cheyette, B.N.R., Hartenstein, V., Zipursky, S.L., and Gruss, P. (1995). Homeobox genes and connective tissue patterning. Development 121, 693-705.

Cheyette, B.N.R., Waxman, J.S., Miller, J.R., Takemaru, K.I., Sheldahl, L.C., Khlebtsova, N., Fox, E.P., Earnest, T., and Moon, R.T. (2002) Dapper, a Dishevelled-Associated Antagonist of beta-catenin and JNK Signaling, is Required for Notochord Formation. Developmental Cell 2, 449-461.

Cheyette, B.N.R., and Moon, R.T. (2003) Wnt Protein Family. in Encyclopedia of Hormones, Helen L. Henry and Anthony W. Norman, editors. Academic Press, San Diego.

Khlebtsova, N., Hung, L.W., Cheyette, B.N.R., Miller, J.R., Moon, R.T., and Earnest, T.N. The Dishevelled PDZ domain exhibits conformational flexibility in response to target binding. In preparation.