Laguna Ariadna, Aranda Sergi, Barallobre María José, Barhoum Rima, Fernández Eduardo, Fotaki Vassiliki, Delabar Jean Maurice, de la Luna Susana, de la Villa Pedro, Arbonés Maria L
Center for Genomic Regulation, UPF, 08003 Barcelona, Spain.
Dev Cell. 2008 Dec;15(6):841-53. doi: 10.1016/j.devcel.2008.10.014.
The precise regulation of programmed cell death is critical for the normal development of the nervous system. We show here that DYRK1A (minibrain), a protein kinase essential for normal growth, is a negative regulator of the intrinsic apoptotic pathway in the developing retina. We provide evidence that changes in Dyrk1A gene dosage in the mouse strongly alter the cellularity of inner retina layers and result in severe functional alterations. We show that DYRK1A does not affect the proliferation or specification of retina progenitor cells, but rather regulates the number of cells that die by apoptosis. We demonstrate that DYRK1A phosphorylates caspase-9 on threonine residue 125, and that this phosphorylation event is crucial to protect retina cells from apoptotic cell death. Our data suggest a model in which dysregulation of the apoptotic response in differentiating neurons participates in the neuropathology of diseases that display DYRK1A gene-dosage imbalance effects, such as Down's syndrome.
程序性细胞死亡的精确调控对于神经系统的正常发育至关重要。我们在此表明，DYRK1A（小头畸形），一种对正常生长至关重要的蛋白激酶，是发育中的视网膜内源性凋亡途径的负调节因子。我们提供的证据表明，小鼠中Dyrk1A基因剂量的变化强烈改变了视网膜内层的细胞数量，并导致严重的功能改变。我们表明，DYRK1A不影响视网膜祖细胞的增殖或分化，而是调节因凋亡而死亡的细胞数量。我们证明，DYRK1A使半胱天冬酶-9的苏氨酸残基125磷酸化，并且该磷酸化事件对于保护视网膜细胞免于凋亡性细胞死亡至关重要。我们的数据提出了一个模型，其中分化神经元中凋亡反应的失调参与了表现出DYRK1A基因剂量失衡效应的疾病的神经病理学，例如下唐氏综合征。
