Park Jung-Min, Kohn Matthew J, Bruinsma Monique W, Vech Claire, Intine Robert V, Fuhrmann Stacy, Grinberg Alex, Mukherjee Ipsita, Love Paul E, Ko Minoru S, DePamphilis Melvin L, Maraia Richard J
Laboratory of Molecular Growth Regulation, National Institute of Child Health and Human Development, 31 Center Drive, Bldg. 31, Rm. 2A25, Bethesda, MD 20892-2426, USA.
Mol Cell Biol. 2006 Feb;26(4):1445-51. doi: 10.1128/MCB.26.4.1445-1451.2006.
The La protein is a target of autoantibodies in patients suffering from Sjögren's syndrome, systemic lupus erythematosus, and neonatal lupus. Ubiquitous in eukaryotes, La functions as a RNA-binding protein that promotes the maturation of tRNA precursors and other nascent transcripts synthesized by RNA polymerase III as well as other noncoding RNAs. La also associates with a class of mRNAs that encode ribosome subunits and precursors to snoRNAs involved in ribosome biogenesis. Thus, it was surprising that La is dispensable in the yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, the organisms from which it has been characterized most extensively. To determine whether La is essential in mammals and if so, at which developmental stage it is required, mice were created with a disrupted La gene, and the offspring from La+/-intercrosses were analyzed. La-/- offspring were detected at the expected frequency among blastocysts prior to implantation, whereas no nullizygotes were detected after implantation, indicating that La is required early in development. Blastocysts derived from La+/- intercrosses yielded 38 La+/+ and La+/- embryonic stem (ES) cell lines but no La-/- ES cell lines, suggesting that La contributes a critical function toward the establishment or survival of ES cells. Consistent with this, La-/- blastocyst outgrowths revealed loss of the inner cell mass (ICM). The results indicate that in contrast to the situation in yeasts, La is essential in mammals and is one of a limited number of genes required as early as the development of the ICM.
La蛋白是干燥综合征、系统性红斑狼疮和新生儿狼疮患者自身抗体的靶标。La在真核生物中广泛存在，作为一种RNA结合蛋白，促进tRNA前体以及由RNA聚合酶III合成的其他新生转录本和其他非编码RNA的成熟。La还与一类编码核糖体亚基的mRNA以及参与核糖体生物发生的snoRNA前体相关联。因此，令人惊讶的是，La在酿酒酵母和粟酒裂殖酵母这两种对其研究最为广泛的生物中是可有可无的。为了确定La在哺乳动物中是否必不可少，如果是，在哪个发育阶段需要它，研究人员构建了La基因缺失的小鼠，并对La+/-杂交后代进行了分析。在植入前的囊胚中，La-/-后代以预期频率被检测到，而在植入后未检测到纯合缺失个体，这表明La在发育早期是必需的。来自La+/-杂交的囊胚产生了38个La+/+和La+/-胚胎干细胞（ES）系，但没有La-/- ES细胞系，这表明La对ES细胞的建立或存活起着关键作用。与此一致的是，La-/-囊胚的体外生长显示内细胞团（ICM）缺失。结果表明，与酵母中的情况不同，La在哺乳动物中是必不可少的，并且是早在ICM发育阶段就需要的少数基因之一。
