Li E, Sucov H M, Lee K F, Evans R M, Jaenisch R
Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge 02142.
Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1590-4. doi: 10.1073/pnas.90.4.1590.
Three unlinked genes encode receptors for retinoic acid (RAR alpha, -beta, and -gamma). Each gene expresses two major protein isoforms differing in the amino terminal A domain by alternative promoter use, fused to common exons encoding most of the receptor protein. The two RAR alpha transcripts (RAR alpha 1 and -alpha 2) are differentially expressed and evolutionarily conserved, as are the RAR beta and -gamma transcripts, suggesting that each isoform may have specific functions in the development of animals. To address the biological function of the alpha 1 receptor, we have disrupted the portion of the RAR alpha gene encoding this isoform by homologous recombination in mouse embryonic stem cells. Surprisingly, offspring homozygous for this mutation were viable and showed no apparently altered phenotype. RNA analysis confirmed that the RAR alpha 1 transcript was absent in homozygous tissues, and no evidence for a compensatory increase of RAR alpha 2 or of another RAR gene was obtained to account for the vitality of the mutant animals. These results clearly demonstrate that loss of RAR alpha 1 function does not disrupt embryonic development and argue for combinatorial or overlapping functions among the RAR isoforms.
三个不连锁的基因编码视黄酸受体（RARα、-β和-γ）。每个基因通过使用不同的启动子表达两种主要的蛋白质异构体，它们在氨基末端A结构域有所不同，并与编码大部分受体蛋白的共同外显子融合。两种RARα转录本（RARα1和-α2）差异表达且在进化上保守，RARβ和-γ转录本也是如此，这表明每种异构体在动物发育中可能具有特定功能。为了研究α1受体的生物学功能，我们通过在小鼠胚胎干细胞中进行同源重组，破坏了RARα基因中编码该异构体的部分。令人惊讶的是，该突变的纯合子后代是有活力的，且没有表现出明显改变的表型。RNA分析证实，纯合组织中不存在RARα1转录本，也没有获得RARα2或其他RAR基因代偿性增加的证据来解释突变动物的活力。这些结果清楚地表明，RARα1功能的丧失不会破坏胚胎发育，并支持RAR异构体之间存在组合或重叠功能的观点。
