During 1996-2002, we cloned and characterized WNT2B (WNT13), WNT3, WNT3A, WNT5B, WNT6, WNT7B, WNT8A, WNT8B, WNT9A (WNT14), WNT9B (WNT14B), WNT10A, WNT10B, WNT11, FZD1, FZD2, FZD3, FZD4, FZD5, FZD6, FZD7, FZD8, FZD10, FRAT1, FRAT2, NKD1, NKD2, VANGL1, RHOU (ARHU), RHOV (ARHV), GIPC2, GIPC3, FBXW11 (ßTRCP2), SOX17, and TCF7L1 (TCF3) by using molecular biology. During 2003-2004, we identified and characterized PRICKLE1, PRICKLE2, DACT1 (DAPPER1), DACT2 (DAPPER2), DAAM2, and BCL9L by using bioinformatics. In 2005, we performed comparative genomics analyses on WNT signaling molecules. The TCF3 article is one of the core papers for the comprehensive characterization of "human WNT-ome" in my laboratory. In addition, there has been an explosion of WNT research projects in the fields of oncology, developmental biology, stem-cell biology, and regenerative medicine. I think that these factors contributed to the high citation rate of our papers in the field of clinical medicine.

The major contribution of our work is the comprehensive cloning and characterization of human genes encoding WNT signaling molecules. In 2002, based on our "human WNT-ome" project, we developed cDNA-PCR system to detect WNT signaling molecules. We investigated expression profiles of WNT signaling molecules in human gastric cancer, esophageal cancer, and the dynamic transcriptional regulation of WNT signaling molecules in neuronal stem cells. Recently, SuperArray Bioscience Corporation developed a microarray system to detect WNT signaling molecules. Because the WNT signaling pathway is implicated in carcinogenesis and embryogenesis, the outcome of our "human WNT-ome" project would be applied for the identification of novel tumor markers and novel stem cell markers, and also for the systems biology of human cancers as well as human stem cells.

Before 1995, I was working on FGF signaling molecules implicated in the morphogenesis and carcinogenesis of the gastrointestinal tract. The American microbiologist Dr. Harold E. Varmus and his colleagues at the University of California School of Medicine in San Francisco elucidated the cross talk between FGF and WNT signaling molecules in the MMTV-induced mouse mammary carcinogenesis model. Varmus and his co-researcher J. Michael Bishop discovered the cellular origin of retroviral oncogenes, for which they were awarded the 1989 Nobel Prize in Physiology or Medicine. From 1993 to 1999 he was Director of the NIH. I had gotten interested in the WNT signaling pathway, and I had worked in the Varmus Laboratory at NIH during 1996 and 1997. In those days, WNT research was carried out using model animals—such as Drosophila, Xenopus, and mouse. Only limited amounts of information on human WNT signaling molecules was available in 1997. Because the biological functions of orthologous genes within the human genome and model-animal genomes are divergent mainly due to the protein evolution and the promoter evolution, I thought that a comprehensive characterization of human WNT signaling molecules is essential for the clinical application of the basic research on the WNT signaling pathway. Therefore, I started the "human WNT-ome" project in 1997 in my laboratory.

Comprehensive characterization of "human WNT-ome" would be the starting platform to elucidate the mechanism of human diseases, and also to develop new diagnostics and therapeutics for human diseases. In particular, antibodies, RNAi, and small molecular compounds targeting for WNT signaling molecules would be developed in the future based on our "human WNT-ome" project.

Dr. Masaru Katoh
National Cancer Center Research Institute
Genetics and Cell Biology Section
Division of Genetics
Tokyo, Japan

Related Links:
•	J. Michael Bishop
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