Katoh Masaru
Genetics and Cell Biology Section, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Stem Cell Rev. 2007 Jan;3(1):30-8. doi: 10.1007/s12015-007-0006-6.
The biological functions of some orthologs within the human genome and model-animal genomes are evolutionarily conserved, but those of others are divergent due to protein evolution and promoter evolution. Because WNT signaling molecules play key roles during embryogenesis, tissue regeneration and carcinogenesis, the author's group has carried out a human WNT-ome project for the comprehensive characterization of human genes encoding WNT signaling molecules. From 1996 to 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/betaTRCP2, SOX17, TCF7L1/TCF3, and established a cDNA-PCR system for snap-shot and dynamic analyses on the WNT-transcriptome. In 2003, we identified and characterized PRICKLE1, PRICKLE2, DACT1/DAPPER1, DACT2/DAPPER2, DAAM2, and BCL9L. After completion of the human WNT-ome project, we have been working on the stem cell signaling network. WNT signals are transduced to beta-catenin, NLK, NFAT, PKC, JNK and RhoA signaling cascades. FGF20, JAG1 and DKK1 are target genes of the WNT-beta-catenin signaling cascade. Cross-talk of WNT and FGF signaling pathways potentiates beta-catenin and NFAT signaling cascades. BMP signals induce IHH upregulation in co-operation with RUNX. Hedgehog signals induce upregulation of SFRP1, JAG2 and FOXL1, and then FOXL1 induces BMP4 upregulation. The balance between WNT-FGF-Notch and BMP-Hedgehog signaling networks is important for the maintenance of homoestasis among stem and progenitor cells. Disruption of the stem cell signaling network results in pathological conditions, such as congenital diseases and cancer.
人类基因组和模式动物基因组中一些直系同源基因的生物学功能在进化上是保守的，但其他一些直系同源基因的功能由于蛋白质进化和启动子进化而发生了分歧。由于WNT信号分子在胚胎发生、组织再生和癌症发生过程中发挥关键作用，作者所在的研究团队开展了一项人类WNT组计划，旨在全面表征编码WNT信号分子的人类基因。1996年至2002年，我们克隆并鉴定了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/betaTRCP2、SOX17、TCF7L1/TCF3，并建立了用于对WNT转录组进行快速快照和动态分析的cDNA-PCR系统。2003年，我们鉴定并表征了PRICKLE1、PRICKLE2、DACT1/DAPPER1、DACT2/DAPPER2、DAAM2和BCL9L。在完成人类WNT组计划后，我们一直在研究干细胞信号网络。WNT信号被转导至β-连环蛋白、NLK、NFAT、PKC、JNK和RhoA信号级联反应。FGF20、JAG1和DKK1是WNT-β-连环蛋白信号级联反应的靶基因。WNT和FGF信号通路的相互作用增强了β-连环蛋白和NFAT信号级联反应。BMP信号与RUNX协同诱导IHH上调。Hedgehog信号诱导SFRP1、JAG2和FOXL1上调，然后FOXL1诱导BMP4上调。WNT-FGF-Notch和BMP-Hedgehog信号网络之间的平衡对于维持干细胞和祖细胞之间的稳态很重要。干细胞信号网络的破坏会导致诸如先天性疾病和癌症等病理状况。
