Arron Joseph R, Winslow Monte M, Polleri Alberto, Chang Ching-Pin, Wu Hai, Gao Xin, Neilson Joel R, Chen Lei, Heit Jeremy J, Kim Seung K, Yamasaki Nobuyuki, Miyakawa Tsuyoshi, Francke Uta, Graef Isabella A, Crabtree Gerald R
Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA.
Nature. 2006 Jun 1;441(7093):595-600. doi: 10.1038/nature04678. Epub 2006 Mar 22.
Trisomy 21 results in Down's syndrome, but little is known about how a 1.5-fold increase in gene dosage produces the pleiotropic phenotypes of Down's syndrome. Here we report that two genes, DSCR1 and DYRK1A , lie within the critical region of human chromosome 21 and act synergistically to prevent nuclear occupancy of NFATc transcription factors, which are regulators of vertebrate development. We use mathematical modelling to predict that autoregulation within the pathway accentuates the effects of trisomy of DSCR1 and DYRK1A, leading to failure to activate NFATc target genes under specific conditions. Our observations of calcineurin-and Nfatc-deficient mice, Dscr1- and Dyrk1a-overexpressing mice, mouse models of Down's syndrome and human trisomy 21 are consistent with these predictions. We suggest that the 1.5-fold increase in dosage of DSCR1 and DYRK1A cooperatively destabilizes a regulatory circuit, leading to reduced NFATc activity and many of the features of Down's syndrome. More generally, these observations suggest that the destabilization of regulatory circuits can underlie human disease.
21三体导致唐氏综合征，但对于基因剂量增加1.5倍如何产生唐氏综合征的多效性表型却知之甚少。在此我们报告，两个基因DSCR1和DYRK1A位于人类21号染色体的关键区域，并协同作用以阻止NFATc转录因子进入细胞核，NFATc转录因子是脊椎动物发育的调节因子。我们使用数学模型预测，该信号通路内的自动调节会加剧DSCR1和DYRK1A三体的影响，导致在特定条件下无法激活NFATc靶基因。我们对钙调神经磷酸酶和Nfatc缺陷小鼠、Dscr1和Dyrk1a过表达小鼠、唐氏综合征小鼠模型以及人类21三体的观察结果与这些预测一致。我们认为，DSCR1和DYRK1A剂量增加1.5倍共同破坏了一个调节回路，导致NFATc活性降低以及唐氏综合征的许多特征。更普遍地说，这些观察结果表明调节回路的破坏可能是人类疾病的基础。
