Molecular Genetics Research Laboratory, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
Genes Dev. 2013 Dec 15;27(24):2708-21. doi: 10.1101/gad.226381.113.
Down's syndrome (DS), a major genetic cause of mental retardation, arises from triplication of genes on human chromosome 21. Here we show that DYRK1A (dual-specificity tyrosine-phosphorylated and -regulated kinase 1A) and DSCR1 (DS critical region 1), two genes lying within human chromosome 21 and encoding for a serine/threonine kinase and calcineurin regulator, respectively, are expressed in neural progenitors in the mouse developing neocortex. Increasing the dosage of both proteins in neural progenitors leads to a delay in neuronal differentiation, resulting ultimately in alteration of their laminar fate. This defect is mediated by the cooperative actions of DYRK1A and DSCR1 in suppressing the activity of the transcription factor NFATc. In Ts1Cje mice, a DS mouse model, dysregulation of NFATc in conjunction with increased levels of DYRK1A and DSCR1 was observed. Furthermore, counteracting the dysregulated pathway ameliorates the delayed neuronal differentiation observed in Ts1Cje mice. In sum, our findings suggest that dosage of DYRK1A and DSCR1 is critical for proper neurogenesis through NFATc and provide a potential mechanism to explain the neurodevelopmental defects in DS.
唐氏综合征（DS）是智力障碍的主要遗传原因，源于人类 21 号染色体上基因的三倍体。在这里，我们发现 DYRK1A（双特异性酪氨酸磷酸化和调节激酶 1A）和 DSCR1（DS 关键区域 1）这两个基因都位于人类 21 号染色体上，分别编码丝氨酸/苏氨酸激酶和钙调神经磷酸酶调节剂，在发育中的小鼠新皮层的神经祖细胞中表达。在神经祖细胞中增加这两种蛋白的剂量会导致神经元分化延迟，最终改变它们的层状命运。这种缺陷是由 DYRK1A 和 DSCR1 协同作用抑制转录因子 NFATc 的活性介导的。在 Ts1Cje 小鼠，一种 DS 小鼠模型中，观察到 NFATc 的失调与 DYRK1A 和 DSCR1 水平的升高有关。此外，拮抗失调途径可以改善 Ts1Cje 小鼠中观察到的神经元分化延迟。总之，我们的研究结果表明，DYRK1A 和 DSCR1 的剂量通过 NFATc 对正常神经发生至关重要，并为解释 DS 中的神经发育缺陷提供了潜在的机制。
