OHSU

Graduate Studies Faculty

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Marcel Wehrli, Ph.D.

Associate Professor
Admin Unit: SOM-Cell & Developmental Biology Department
Phone: 503-494-0245
Lab Phone: 503-494-5150
Fax: 503-494-4253
Office: BSAC 5590
Mail Code: L215
Programs:
Cell & Developmental Biology
Neuroscience Graduate Program
Program in Molecular & Cellular Biosciences
Cancer Biology
Research Interests:
developmental biology genetics signal transduction cell-cell communication morphogen gradients receptor Wnt/Wingless Arrow/LRP Axin protein complex formation and its regulation medical cancer bone mass » PubMed Listing
Preceptor Rotations
Dr. Wehrli has not indicated availability for preceptor rotations at this time.
Faculty Mentorship
Dr. Wehrli has not indicated availability as a mentor at this time.
Profile

Summary of Current Research

Developmental biology has beautifully demonstrated that specific signals direct cells to differentiate into specific cell types. Subsequently these differentiating cells form the organs and tissues of our bodies. Genetics and molecular biology have provided the necessary tools to look in vivo at the loss of those signals and the resulting aberrations of the differentiation program. Much of this work has been accomplished, not in humans, of course, but in model organisms, such as the fruit fly, Drosophila melanogaster. Through molecular genetic approaches, a relatively small number of pathways have been identified that, singly or in combination, control the differentiation of specific cell types. Strikingly, these pathways, as well as their impact on cellular differentiation, have been conserved from flies through humans.

One of the most important pathways in development is the Wnt pathway. First identified in the fly, the Wnt pathway is important not only during development of flies, worms, mice and humans, but in the etiology of a number of human cancers. Wnts are glycoproteins that are secreted from cells and can function as long- or short-range signals. On a responding cell, the Wnt signal is received at the membrane by receptors of the Frizzled family, a class of seven-pass transmembrane proteins. Activation of an intracellular signaling cascade culminates in the accumulation of beta-catenin/Armadillo, which translocates to the nucleus and, together with members of the Lef/Tcf-family of DNA-binding proteins, results in a transcriptional response in signaled cells. However, our understanding how precisely Wnt is received at the cell membrane and signaling initiated on the cytoplasmic side remains unclear. We have a unique handle on this question.

Using fly genetics, we identified a novel component acting in the Wnt pathway, a single-pass transmembrane protein called Arrow. This is a candidate co-receptor for the Wnt ligand (together with Frizzleds) and its identification and cloning now allows us to investigate how a signaling complex is assembled. For instance, we recently found that the cytoplasmic tail of Arrow interacts with the scaffolding protein Axin. Axin is thought to function by binding beta-catenin/Armadillo, thereby preventing it from activating transcription in the nucleus. Our model now is that Arrow may release Armadillo from the Axin complex, thereby eliciting a signal. We can now address this and other key questions concerning the Wnt signaling pathway. For example, we generated an Arrow construct that in vivo greatly potentiates signaling. This construct still depends on signaling. Another construct activates the intracellular signaling cascade in vivo independent of ligand. Thus it contains all the elements necessary to assemble the signaling complex, and thereby functions as an activated receptor. A molecular dissection of this activated receptor will shed light on the signaling mechanism.

Please see the Cell and Developmental Biology web site for a more detailed description of our interests at

http://www.ohsu.edu/cellbio/faculty/faculty%20pages/wehrli.html