Park Chang Sin, Zhong Ling, Tang Shao-Jun
Department of Neurobiology and Behavior, Center for Neurobiology of Learning and Memory, University of California, Irvine, California, USA.
J Neurosci Res. 2009 Nov 1;87(14):3107-19. doi: 10.1002/jnr.22134.
Neurofibromatosis 1 (NF1) is a common single-gene disorder that causes learning impairments in patients. Neurofibromin encoded by the NF1 causal gene regulates Ras/MAPK and cAMP signaling pathways. These signaling pathways play critical roles in controlling gene transcription during synaptic plasticity and memory formation. We hypothesized that NF1 mutations disturb the expression of genes important for memory formation. To test this hypothesis, we performed DNA microarray analysis on the hippocampus of NF1(+/-) mice, the mouse model for NF1 learning disabilities. Our results indicated that genes involved in a wide spectrum of biological processes are dysregulated in the NF1(+/-) hippocampus. Many of the NF1-affected genes play critical roles in synaptic plasticity, such as Rabs, synaptotagmins, NMDAR1, CaMKII, and CREB1. Because NF1-associated learning disabilities can be reversed by lovastatin, we also determined the effect of lovastatin treatment on genome-wide expression patterns of the NF1(+/-) hippocampus. We found that lovastatin altered the expression of a large number of genes, including those disturbed by NF1 mutations. Our results reveal a genome-wide overview of the molecular abnormalities in the NF1(+/-) hippocampus and should be useful for further identifying the novel molecular pathways that cause NF1 learning deficits.
神经纤维瘤病1型（NF1）是一种常见的单基因疾病，可导致患者出现学习障碍。NF1致病基因编码的神经纤维瘤蛋白调节Ras/MAPK和cAMP信号通路。这些信号通路在突触可塑性和记忆形成过程中控制基因转录方面发挥着关键作用。我们推测NF1突变会干扰对记忆形成至关重要的基因的表达。为了验证这一假设，我们对NF1（+/-）小鼠（NF1学习障碍的小鼠模型）的海马体进行了DNA微阵列分析。我们的结果表明，参与广泛生物过程的基因在NF1（+/-）海马体中表达失调。许多受NF1影响的基因在突触可塑性中发挥关键作用，如Rabs、突触结合蛋白、NMDAR1、CaMKII和CREB1。由于洛伐他汀可以逆转与NF1相关的学习障碍，我们还确定了洛伐他汀治疗对NF1（+/-）海马体全基因组表达模式的影响。我们发现洛伐他汀改变了大量基因的表达，包括那些受NF1突变干扰的基因。我们的结果揭示了NF1（+/-）海马体分子异常的全基因组概况，这对于进一步确定导致NF1学习缺陷的新分子途径应该是有用的。
