Transgenic mouse in vivo library of human down syndrome critical region 1:: Association between DYRK1A overexpression, brain development abnormalities, and cell cycle protein alteration

被引:78
作者
Branchi, I
Bichler, Z
Minghetti, L
Delabar, JM
Malchiodi-Albedi, F
Gonzalez, MC
Chettouh, Z
Nicolini, A
Chabert, C
Smith, DJ
Rubin, EM
Migliore-Samour, D
Alleva, E
机构
[1] Ist Super Sanita, Dept Cell Biol & Neurosci, Sect Behav Neurosci, I-00161 Rome, Italy
[2] Ruhr Univ Bochum, Lehrstuhl Mol Neurobiochem, Bochum, Germany
[3] Inst Transgenose, CNRS, FRE 2358, Orleans, France
[4] Univ Paris, Paris, France
[5] Univ Calif Los Angeles, Dept Mol & Med Pharmacol, Los Angeles, CA USA
[6] Univ Calif Berkeley, Lawrence Berkeley Lab, Genome Sci Dept, Berkeley, CA 94720 USA
关键词
brain size; CREB; development; Down syndrome; DYRK1A; FKHR; neuronal size;
D O I
10.1093/jnen/63.5.429
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Down syndrome is the most frequent genetic cause of mental retardation, having an incidence of I in 700 live births. In the present study we used a transgenic mouse in vivo library consisting of 4 yeast artificial chromosome (YAC) transgenic mouse lines, each bearing a different fragment of the Down syndrome critical region 1 (DCR-1), implicated in brain abnormalities characterizing this pathology. The 152F7 fragment, in addition to genes also located on the other DCR-1 fragments, bears the DYRK1A gene, encoding for a serine-threonine kinase. The neurobehavioral analysis of these mouse lines showed that DYRK1A overexpressing 152177 mice but not the other lines display learning impairment and hyperactivity during development. Additionally, 152F7 mice display increased brain weight and neuronal size. At a biochemical level we found DYRK1A overexpression associated with a development-dependent increase in phosphorylation of the transcription factor FKHR and with high levels of cyclin B 1, suggesting for the first time in vivo a correlation between DYRK1A overexpression and cell cycle protein alteration. In addition, we found an altered phosphorylation of transcription factors of CREB family. Our findings support a role of DYRK1A overexpression in the neuronal abnormalities seen in Down syndrome and suggest that this pathology is linked to altered levels of proteins involved in the regulation of cell cycle.
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收藏
页码:429 / 440
页数:12
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