Yamaki A, Noda S, Kudoh J, Shindoh N, Maeda H, Minoshima S, Kawasaki K, Shimizu Y, Shimizu N
Department of Molecular Biology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, 160, Japan.
Genomics. 1996 Jul 1;35(1):136-43. doi: 10.1006/geno.1996.0332.
We have recently isolated a human homolog (hSIM) of the Drosophila single-minded (sim) gene from the Down syndrome critical region of chromosome 21 using the exon trapping method. The Drosophila sim gene encodes a transcription factor that regulates the development of the central nervous system midline cell lineage. To elucidate the structure of the mammalian SIM protein, we have isolated cDNA clones from a mouse embryo cDNA library. The cDNA clones encode a polypeptide of 657 amino acids with a bHLH (basic-helix-loop-helix) domain, characteristic of a large family of transcription factors, and a PAS (Per-Arnt-Sim) domain in the amino-terminal half region. Both of these domains have striking sequence homology with human SIM and Drosophila SIM proteins. In contrast, the carboxy-terminal half of the mouse SIM protein consists of a proline-rich region with no sequence homology to the Drosophila SIM protein. A similar proline-rich domain is known for the activator domain of a number of transcription factors. Whole-mount embryo in situ hybridization experiments revealed that the SIM mRNA is expressed prominently in the diencephalon of mouse embryos at 8-9.5 days postcoitum. The structural characteristics of the mouse SIM protein and its expression in the diencephalon during embryogenesis strongly suggest that the newly isolated mammalian SIM homolog may play a critical role in the development of the mammalian central nervous system. We propose that the human SIM gene may be one of the pathogenic genes of Down syndrome.
我们最近利用外显子捕获法，从21号染色体的唐氏综合征关键区域分离出了果蝇单 minded（sim）基因的人类同源物（hSIM）。果蝇sim基因编码一种转录因子，该转录因子调节中枢神经系统中线细胞谱系的发育。为了阐明哺乳动物SIM蛋白的结构，我们从小鼠胚胎cDNA文库中分离出了cDNA克隆。这些cDNA克隆编码一个657个氨基酸的多肽，该多肽在氨基末端半区具有bHLH（碱性-螺旋-环-螺旋）结构域，这是一大类转录因子的特征结构域，以及一个PAS（Per-Arnt-Sim）结构域。这两个结构域与人类SIM蛋白和果蝇SIM蛋白都有显著的序列同源性。相比之下，小鼠SIM蛋白的羧基末端半区由一个富含脯氨酸的区域组成，该区域与果蝇SIM蛋白没有序列同源性。许多转录因子的激活结构域都有类似的富含脯氨酸的结构域。全胚胎原位杂交实验显示，在妊娠8-9.5天的小鼠胚胎中，SIM mRNA在间脑中大量表达。小鼠SIM蛋白的结构特征及其在胚胎发生过程中间脑中的表达强烈表明，新分离的哺乳动物SIM同源物可能在哺乳动物中枢神经系统的发育中起关键作用。我们推测人类SIM基因可能是唐氏综合征的致病基因之一。
