Katoh Masaru
Genetics and Cell Biology Section, Genetics Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045, Japan.
Int J Mol Med. 2002 Dec;10(6):683-7.
NT2/NTera2 cells, derived from human embryonal tumor, differentiate into neuronal cells after treatment with all-trans-retinoic acid (ATRA). We have cloned and characterized 13 out of 19 human WNT genes, and also 9 out of 10 human Frizzled (FZD) genes encoding seven-transmembrane-type WNT receptors, which are potent targets for pharmacogenomics in the post-genomic era, especially in the field of regenerative medicine and clinical oncology. Because WNT signals are implicated in morphogenesis of neural tissues, regulation of 19 WNT genes and 10 FZD genes during the early phase of neuronal differentiation in NT2 cells is reviewed. Multiple WNTs and FZDs are expressed in NT2 cells. WNT2B/WNT13 gene encode 2 isoforms due to alternative splicing of alternative promoter type, and WNT2B isoform 2 (WNT2B2) rather than WNT2B isoform 1 (WNT2B1) is expressed in NT2 cells. WNT3A, WNT8A, WNT8B, WNT10B and WNT11 are down-regulated in NT2 cells after ATRA treatment, while WNT2, WNT7B and WNT14B are up-regulated. FZD4 and FZD10 are up-regulated in NT2 cells after ATRA treatment. Expression of multiple WNT signaling molecules are dramatically changed during the early phase of neuronal differentiation in NT2 cells. Each WNT activates the beta-catenin - TCF pathway, the JNK pathway or the Ca2+-releasing pathway in NT2 cells, and summed effects of multiple WNTs might determine the fate of NT2 cells (self-renewal or differentiation) through switching intracellular WNT signaling pathways. The author proposes the threshold model of WNT action.
NT2/NTera2细胞源自人类胚胎肿瘤，经全反式维甲酸（ATRA）处理后可分化为神经细胞。我们已克隆并鉴定了19个人类WNT基因中的13个，以及10个人类卷曲蛋白（FZD）基因中的9个，这些基因编码七跨膜型WNT受体，是后基因组时代药物基因组学的重要靶点，尤其在再生医学和临床肿瘤学领域。由于WNT信号与神经组织的形态发生有关，本文综述了NT2细胞神经元分化早期19个WNT基因和10个FZD基因的调控情况。NT2细胞中表达多种WNTs和FZDs。WNT2B/WNT13基因由于可变启动子类型的可变剪接而编码2种异构体，NT2细胞中表达的是WNT2B异构体2（WNT2B2）而非WNT2B异构体1（WNT2B1）。ATRA处理后，NT2细胞中WNT3A、WNT8A、WNT8B、WNT10B和WNT11表达下调，而WNT2、WNT7B和WNT14B表达上调。ATRA处理后，NT2细胞中FZD4和FZD10表达上调。在NT2细胞神经元分化早期，多种WNT信号分子的表达发生显著变化。每个WNT在NT2细胞中激活β-连环蛋白 - TCF途径、JNK途径或Ca2+释放途径，多种WNTs的综合作用可能通过切换细胞内WNT信号通路来决定NT2细胞的命运（自我更新或分化）。作者提出了WNT作用的阈值模型。
