Research Interests
The Wnt signaling pathway, a highly conserved pathway in the animal kingdom, plays key roles in the integral development of an organism. Mutations that disrupt this signaling pathway lead to profound developmental defects in a number of tissues and organs, such as central nervous system, kidney, reproductive organs, limbs, and placenta. When uncontrolled, this signaling pathway also causes several human cancers, such as melanoma and colon cancers. Previous studies by a number of groups have identified several essential intracellular components in transducing the signal into the nucleus to initiate expression of genes that control the proliferation, differentiation and migration of the cells. However, the biochemical mechanism of Wnt signal transduction mediated by the receptors remain unclear. The research interests in the lab aim to understand the molecular mechanisms by which Wnt signals are transduced in a regulated manner and how disruption of this mechanism leads to developmental defects.
Our current researches focus on:
1) Determining the mechanism by which the receptors transduce the Wnt signals downstream;
2) Characterizing the biochemical and structural properties of Wnt proteins through systematic mutagenesis and functional assays, with the long-term goal of solving the structure of a Wnt protein;
3) Screen for molecules or chemical agents capable of modulating Wnt signaling;
4) Identifying factors governing the specificity of interactions between Wnts and their receptors;
5) Identifying genes responsive to Wnt signaling.
Selected Publications
Jen-Chih Hsieh, L. Lee, L. Zhang, S. Wefer, K. Brown, C. DeRossi, M.E. Wines, T. Rosenquist, and B.C. Holdener (2003) Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell 112, 355-367. Full Text Article
A. Dabdoub, M.J. Donohue, A. Brennan, V. Wolf, M. Montcouquiol, D.A. Sassoon, Jen-Chih Hsieh, J.S. Rubin, P.C. Salina, and M.W. Kelly (2003) Wnt signaling mediates reorientation of outer hair cell stereociliary bundles in the mammalian cochlea. Development 130, 2375-2384. Full Text Article.
L. Gunhaga, M. Marklund, M. Sjödal, Jen-Chih Hsieh, T.M. Jessel and T. Edlund (2003) Specification of dorsal telencephalic character by sequential Wnt and FGF signaling. Nature Neuroscience, July, 2003.
C. Wissmann, P. J. Wild, S. Kaiser, S. Roepcke, R. Steohr, M. Woenckhaus, G. Kristiansen, Jen-Chih Hsieh, F. Hofstaedter, A. Hartmann, R. Knuchel, A. Rosenthal and C. Pilarsky (2003) WIF1 a component of the Wnt pathway is down-regulated in prostate, breast, lung and bladder cancer. J. Pathology, in press.
C. Dann, Jen-Chih Hsieh, A. Rattner, J. Nathans, D. Leahy (2001) Insight into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains. Nature 412, 86-90. Abstract.
Jen-Chih Hsieh, L. Kadjabachian, M. L. Rebbert, A. Rattner, P. M. Smallwood, C. Harryman Samos, R. Nusse, I. B. Dawid, & J. Nathans (1999) A new secreted protein that binds to Wnt proteins and inhibits their activities. Nature 398, 431-436. Abstract
Jen-Chih Hsieh, A. Rattner, P. M. Smallwood, and J. Nathans (1999) Biochemical characterization of Wnt-Frizzled interactions using a soluble, biologically active vertebrate Wnt protein. Proc. Natl. Acad. Sci. USA 96, 3546-3551. Full Text Article
A. Rattner, Jen-Chih Hsieh, P.M. Smallwood, D.J. Gilbert, N.G. Copeland, N.A. Jenkins, and J. Nathans (1997) A family of secreted proteins contains homology to the cysteine-rich ligand-binding domain of frizzled receptors. Proc. Natl. Acad. Sci. USA 94, 2859-2863. Full Text Article
P. Bhanot, M. Brink, C. H. Samos, Jen-Chih Hsieh, Y. Wang, J. P. Macke, D. Andrew, J. Nathans, and R. Nusse (1996) A New member of the frizzled family from Drosophila functions as a Wingless receptor. Nature 382, 225-230. Abstract