Effect of DYRK1A activity inhibition on development of neuronal progenitors isolated from Ts65Dn mice
Effect of DYRK1A activity inhibition on development of neuronal progenitors isolated from Ts65Dn mice
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DOI：
10.1002/jnr.23007
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发表时间：
2012-05-01
影响因子：
4.2
通讯作者：
Frackowiak, Janusz
中科院分区：
文献类型：
--
作者：
Mazur-Kolecka, Bozena;Golabek, Adam;Frackowiak, Janusz
双特异性酪氨酸-（Y）-磷酸化调节激酶1A（DYRK 1A），位于唐氏综合征（DS）的关键区域的基因编码的过度表达，被认为是一个主要的贡献者发育异常的DS。DYRK 1A调节参与神经元定型、分化、成熟和凋亡的许多基因。由于神经发生的改变可能导致DS患者的大脑发育受损和智力低下，因此DYRK 1A活性的药理学正常化被假定为DS治疗。我们测试了去氢骆驼蓬碱（一种特异性DYRK 1A抑制剂）对神经元祖细胞（NPC）发育的影响，这些神经元祖细胞分离自患有节段性16三体（Ts 65 Dn小鼠）的新生小鼠脑室周围区，这是一种过度表达Dyrk 1A的DS小鼠模型。三体不影响NPC在培养中的扩张能力。在迁移和神经元分化的刺激后24小时，NPC显示出Dyrk 1A的表达增加，特别是在三体培养物中。7天后，NPC发育成分化中的神经元和星形胶质细胞的异质群体，这些神经元和星形胶质细胞在细胞核中表达Dyrk 1A。与二体细胞相比，三体NPC表现出过早的神经元分化和增强的？氨基丁酸（GABA）能分化，但星形胶质细胞的发展是不变的。去氢骆驼蓬碱阻止三体NPC的神经元过早成熟，但不加速GABA能发育。在对照NPC中，去氢骆驼蓬碱处理引起NPC的神经元发育改变，类似于Dyrk 1A过表达的三体NPC。这项研究表明，DYRK 1A活性的药理学正常化可能在DS治疗中具有潜在的作用。(C)2012 Wiley Periodicals，Inc.
Overexpression of dual-specificity tyrosine-(Y)-phosphorylation-regulated kinase 1A (DYRK1A), encoded by a gene located in the Down syndrome (DS) critical region, is considered a major contributor to developmental abnormalities in DS. DYRK1A regulates numerous genes involved in neuronal commitment, differentiation, maturation, and apoptosis. Because alterations of neurogenesis could lead to impaired brain development and mental retardation in individuals with DS, pharmacological normalization of DYRK1A activity has been postulated as DS therapy. We tested the effect of harmine, a specific DYRK1A inhibitor, on the development of neuronal progenitor cells (NPCs) isolated from the periventricular zone of newborn mice with segmental trisomy 16 (Ts65Dn mice), a mouse model for DS that overexpresses Dyrk1A by 1.5-fold. Trisomy did not affect the ability of NPCs to expand in culture. Twenty-four hours after stimulation of migration and neuronal differentiation, NPCs showed increased expression of Dyrk1A, particularly in the trisomic cultures. After 7 days, NPCs developed into a heterogeneous population of differentiating neurons and astrocytes that expressed Dyrk1A in the nuclei. In comparison with disomic cells, NPCs with trisomy showed premature neuronal differentiation and enhanced ?-aminobutyric acid (GABA)-ergic differentiation, but astrocyte development was unchanged. Harmine prevented premature neuronal maturation of trisomic NPCs but not acceleration of GABA-ergic development. In control NPCs, harmine treatment caused altered neuronal development of NPCs, similar to that in trisomic NPCs with Dyrk1A overexpression. This study suggests that pharmacological normalization of DYRK1A activity may have a potential role in DS therapy. (C) 2012 Wiley Periodicals, Inc.