Alvarez Enrique, Zhou Wenbo, Witta Samir E, Freed Curt R
Medical Scientist Training Program, University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Gene. 2005 Aug 29;357(1):18-28. doi: 10.1016/j.gene.2005.05.012.
To better understand the development of ventral mesencephalic dopamine neurons, we performed subtractive hybridization screens to find ventral mesencephalic genes expressed at rat embryonic day 10 when these neurons begin to differentiate. The most commonly identified genes in these screens were members of the Bex (Brain expressed X-linked) gene family, rat Bex1 (Rex3), and a novel gene, rat Bex4. After identifying these genes, we then sought to characterize the Bex gene family. Two additional novel Bex genes (human Bex5 and mouse Bex6) were discovered through genomic databases. Bex5 is present in humans and monkeys, but not rodents, while Bex6 exists in mice, but not humans. Bex4 and Bex5 are localized to the X chromosome, are expressed in brain, and are similar in sequence. Bex4 and Bex5 are 54% and 56% identical to human Bex3 (pHGR74, NADE). Mouse Bex6 is on chromosome 16 and is 67% identical to mouse Bex4. Human Bex gene expression was studied with tissue expression arrays probed with specific oligonucleotides. Human Bex1 and Bex2 have similar expression patterns in the central nervous system with high levels in pituitary, cerebellum, and temporal lobe, and Bex1 is widely expressed outside of the central nervous system with high expression in the liver. Human Bex4 is highly expressed in heart, skeletal muscle, and liver, while Bex3 and Bex5 are more widely expressed. The subcellular localization of the Bex proteins varies from nuclear (rat Bex1) to cytoplasmic (rat Bex3, human Bex5, and mouse Bex6) and to both nuclear and cytoplasmic (rat Bex2 and rat Bex4). Rat Bex3, rat Bex4, human Bex5, and mouse Bex6 are degraded by the proteasome, while rat Bex1 or Bex2 are not. Rat Bex3 protein can likely bind transition metals through a histidine-rich domain. Because this gene family was originally named Bex and because these genes are unified by sequence similarity and gene structure, we believe the Bex nomenclature should prevail over nomenclature based on function (NADE) that has not been extended to the other Bex genes. We conclude that the Bex gene family members are highly homologous but differ in their expression patterns, subcellular localization, and degradation by the proteasome.
为了更好地理解腹侧中脑多巴胺神经元的发育过程，我们进行了消减杂交筛选，以寻找在大鼠胚胎第10天（此时这些神经元开始分化）表达的腹侧中脑基因。在这些筛选中最常鉴定出的基因是Bex（脑表达X连锁）基因家族的成员、大鼠Bex1（Rex3）和一个新基因——大鼠Bex4。在鉴定出这些基因后，我们接着试图对Bex基因家族进行表征。通过基因组数据库发现了另外两个新的Bex基因（人类Bex5和小鼠Bex6）。Bex5存在于人类和猴子中，但不存在于啮齿动物中，而Bex6存在于小鼠中，但不存在于人类中。Bex4和Bex5定位于X染色体，在脑中表达，且序列相似。Bex4和Bex5与人类Bex3（pHGR74，NADE）的序列一致性分别为54%和56%。小鼠Bex6位于16号染色体上，与小鼠Bex4的序列一致性为67%。我们用特异性寡核苷酸探针检测的组织表达阵列研究了人类Bex基因的表达。人类Bex1和Bex2在中枢神经系统中的表达模式相似，在垂体、小脑和颞叶中表达水平较高，并且Bex1在中枢神经系统外广泛表达，在肝脏中表达水平较高。人类Bex4在心脏、骨骼肌和肝脏中高表达，而Bex3和Bex5的表达更为广泛。Bex蛋白的亚细胞定位各不相同，从核定位（大鼠Bex1）到胞质定位（大鼠Bex3、人类Bex5和小鼠Bex6），再到核质定位（大鼠Bex2和大鼠Bex4）。大鼠Bex3、大鼠Bex4、人类Bex5和小鼠Bex6可被蛋白酶体降解，而大鼠Bex1或Bex2则不会。大鼠Bex3蛋白可能通过一个富含组氨酸的结构域结合过渡金属。由于这个基因家族最初被命名为Bex，并且这些基因通过序列相似性和基因结构统一起来，我们认为Bex命名法应优先于基于功能（NADE）的命名法，因为基于功能的命名法尚未扩展到其他Bex基因。我们得出结论，Bex基因家族成员高度同源，但在表达模式、亚细胞定位以及被蛋白酶体降解方面存在差异。
