Katoh Masuko, Katoh Masaru
M&M Medical BioInformatics, Hongo 113-0033, Japan.
Int J Mol Med. 2006 May;17(5):795-9.
Nodal and BMP signaling pathways network with WNT signaling pathway during embryogenesis and carcinogenesis. CER1 (Cerberus 1) and GREM3 (CKTSF1B3 or CER2) inhibit NODAL signaling through ACVR1B (ALK4) or ACVR1C (ALK7) to SMAD2 or SMAD3. GREM1 (CKTSF1B1) inhibits BMP signaling through BMPR1A (ALK3), BMPR1B (ALK6) or ACVR1 (ALK2) to SMAD1, SMAD5 or SMAD8. CER1, GREM1 and GREM3 are DAN domain (DAND) family members; however, transcriptional regulation of DAND family members by canonical WNT signaling pathway remains unclear. We searched for the TCF/LEF-binding site within the promoter region of DAND family genes, including CER1, GREM1, GREM2, GREM3 and NBL1. Because triple TCF/LEF-binding sites were identified within human CER1 promoter by using bioinformatics and human intelligence, comparative genomics analyses on CER1 orthologs were further performed. Chimpanzee CER1 gene, encoding 267-amino-acid protein, was identified within NW_111298.1 genome sequence. XM_528542.1 was not a correct coding sequence for chimpanzee CER1. Primate CER1 orthologs were significantly divergent from rodent Cer1 orthologs. Three TCF/LEF-binding sites within human CER1 promoter were conserved in chimpanzee CER1 promoter, two in cow and dog Cer1 promoters, but not in rodent Cer1 promoters. Binding sites for NODAL signaling effectors, SMAD3/SMAD4 and FOXH1, were also conserved among human, chimpanzee, cow and dog CER1 promoters. CER1 orthologs were evolutionarily conserved target of WNT and NODAL signaling pathways in non-rodent mammals. Human CER1 mRNA was expressed in embryonic stem (ES) cells in the undifferentiated state and in the early endodermal lineage. CER1 upregulation in human ES cells leads to Nodal signaling inhibition associated with differentiation of human ES cells. Primate CER1 orthologs, playing a pivotal role during early embryogenesis, underwent protein evolution as well as promoter evolution. These facts indicate that molecular evolution of CER1 orthologs contributes to the significantly divergent scenarios of early embryogenesis in primates and rodents.
在胚胎发育和肿瘤发生过程中，Nodal和BMP信号通路与WNT信号通路形成网络。CER1（Cerberus 1）和GREM3（CKTSF1B3或CER2）通过ACVR1B（ALK4）或ACVR1C（ALK7）抑制NODAL信号传导至SMAD2或SMAD3。GREM1（CKTSF1B1）通过BMPR1A（ALK3）、BMPR1B（ALK6）或ACVR1（ALK2）抑制BMP信号传导至SMAD1、SMAD5或SMAD8。CER1、GREM1和GREM3是DAN结构域（DAND）家族成员；然而，经典WNT信号通路对DAND家族成员的转录调控仍不清楚。我们在DAND家族基因（包括CER1、GREM1、GREM2、GREM3和NBL1）的启动子区域搜索TCF/LEF结合位点。由于通过生物信息学和人工智慧在人类CER1启动子中鉴定出三个TCF/LEF结合位点，因此对CER1直系同源基因进行了比较基因组学分析。在NW_111298.1基因组序列中鉴定出编码267个氨基酸蛋白的黑猩猩CER1基因。XM_528542.1不是黑猩猩CER1的正确编码序列。灵长类动物的CER1直系同源基因与啮齿动物的Cer1直系同源基因有显著差异。人类CER1启动子中的三个TCF/LEF结合位点在黑猩猩CER1启动子中保守，在牛和狗的Cer1启动子中有两个保守，但在啮齿动物的Cer1启动子中不保守。NODAL信号效应器SMAD3/SMAD4和FOXH1的结合位点在人类、黑猩猩、牛和狗CER1启动子中也保守。CER1直系同源基因是在非啮齿动物哺乳动物中WNT和NODAL信号通路在进化上保守的靶点。人类CER1 mRNA在未分化状态的胚胎干细胞和早期内胚层谱系中表达。人类胚胎干细胞中CER1的上调导致与人类胚胎干细胞分化相关的Nodal信号抑制。在早期胚胎发育过程中起关键作用的灵长类动物CER1直系同源基因经历了蛋白质进化以及启动子进化。这些事实表明，CER1直系同源基因的分子进化促成了灵长类动物和啮齿动物早期胚胎发育的显著不同情况。
