Katoh Yuriko, Katoh Masaru
M&M Medical BioInformatics, Hongo 113-0033, Japan.
Int J Mol Med. 2006 May;17(5):951-5.
WNT, Notch, FGF, Hedgehog and BMP signaling pathways network together during embryogenesis, tissue regeneration, and carcinogenesis. BMP2, BMP3, BMP4, BMP5, BMP6, BMP7, BMP8A, BMP8B, BMP10, BMP15, AMH, GDF1, GDF2, GDF3, GDF5, GDF6, GDF7, GDF8, GDF9, GDF10, GDF11, and GDF15 are BMP/GDF family genes within the human genome; however, transcriptional regulation of BMP/GDF family members by the canonical WNT signaling pathway remains unclear. We searched for the TCF/LEF-binding site within the promoter region of BMP/GDF family genes by using bioinformatics and human intelligence. Because four TCF/LEF-binding sites were identified within human GDF10 promoter, comparative genomics analyses on GDF10 orthologs were further performed. Chimpanzee GDF10 gene, encoding a 477-amino-acid protein, was identified within NW_112875.1 genome sequence. AY412135.1 was not the correct coding sequence for chimpanzee GDF10. Chimpanzee GDF10 showed 99.2%, 83.2% and 47.4% total amino-acid identity with human GDF10, mouse Gdf10 and human BMP3, respectively. RASGEF1A-GDF10-PRKG1 locus at human chromosome 10q11 and BMP3-PRKG2-RASGEF1B locus at human chromosome 4q21 were paralogous regions with insertions/deletions and recombination. Human GDF10 mRNA was expressed in fetal cochlea, fetal lung, testis, retina, pineal gland, other neural tissues, head and neck tumors, while mouse Gdf10 mRNA was expressed in fetal liver, inner ear, cerebellum, other neural tissues, prostate and blood vessels. Four TCF/LEF-binding sites in human GDF10 promoter were conserved in chimpanzee GDF10 promoter, but not in the mouse Gdf10 promoter; however, another TCF/LEF-binding site occurred in mouse Gdf10 promoter. Four bHLH-binding sites in human GDF10 promoter were conserved in chimpanzee GDF10 promoter, but only one in mouse Gdf10 promoter. Primate GDF10 promoters were divergent from mouse Gdf10 promoter. Because GDF10 was characterized as a potential target of canonical WNT signaling pathway in neural tissues, GDF10 is one of the targets of systems medicine, especially in the field of regenerative medicine.
WNT、Notch、FGF、Hedgehog和BMP信号通路在胚胎发生、组织再生和肿瘤发生过程中共同构成网络。BMP2、BMP3、BMP4、BMP5、BMP6、BMP7、BMP8A、BMP8B、BMP10、BMP15、AMH、GDF1、GDF2、GDF3、GDF5、GDF6、GDF7、GDF8、GDF9、GDF10、GDF11和GDF15是人类基因组中的BMP/GDF家族基因；然而，经典WNT信号通路对BMP/GDF家族成员的转录调控仍不清楚。我们通过生物信息学和人工分析在BMP/GDF家族基因的启动子区域搜索TCF/LEF结合位点。由于在人类GDF10启动子中鉴定出四个TCF/LEF结合位点，因此对GDF10直系同源基因进行了比较基因组学分析。在NW_112875.1基因组序列中鉴定出编码477个氨基酸蛋白质的黑猩猩GDF10基因。AY412135.1不是黑猩猩GDF10的正确编码序列。黑猩猩GDF10与人类GDF10、小鼠Gdf10和人类BMP3的总氨基酸同一性分别为99.2%、83.2% 和47.4%。人类染色体10q11上的RASGEF1A - GDF10 - PRKG1基因座和人类染色体4q21上的BMP3 - PRKG2 - RASGEF1B基因座是具有插入/缺失和重组的旁系同源区域。人类GDF10 mRNA在胎儿耳蜗、胎儿肺、睾丸、视网膜、松果体、其他神经组织、头颈部肿瘤中表达，而小鼠Gdf10 mRNA在胎儿肝脏、内耳、小脑、其他神经组织、前列腺和血管中表达。人类GDF10启动子中的四个TCF/LEF结合位点在黑猩猩GDF10启动子中保守，但在小鼠Gdf10启动子中不保守；然而，小鼠Gdf10启动子中出现了另一个TCF/LEF结合位点。人类GDF10启动子中的四个bHLH结合位点在黑猩猩GDF10启动子中保守，但在小鼠Gdf10启动子中只有一个保守。灵长类动物GDF10启动子与小鼠Gdf10启动子不同。由于GDF10被鉴定为神经组织中经典WNT信号通路的潜在靶点，因此GDF10是系统医学的靶点之一，尤其是在再生医学领域。
