Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning
Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning
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DOI：
10.1093/hmg/ddv103
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发表时间：
2015-06-15
影响因子：
3.5
通讯作者：
Gutmann, David H.
中科院分区：
文献类型：
--
作者：
Anastasaki, Corina;Woo, Albert S.;Gutmann, David H.
1型神经纤维瘤病（NF 1）是一种常见的常染色体显性遗传性神经系统疾病，其特征在于显著的临床异质性，从恶性肿瘤到认知缺陷。最近的研究已经开始揭示罕见的基因型-表型相关性，表明特定的生殖系NF 1基因突变可能是疾病异质性的一个因素。本研究的目的是确定生殖系NF 1基因突变对与学习相关的脑神经纤维蛋白功能的影响。在此，我们采用人NF 1患者的原代皮肤成纤维细胞，诱导多能干细胞和衍生的神经祖细胞（NPC），以证明NF 1种系突变对神经纤维蛋白的表达有显着的影响。此外，虽然所有NF 1患者NPC表现出RAS激活增加和环AMP生成减少，但多巴胺（DA）水平呈神经纤维蛋白剂量依赖性降低。此外，我们利用了两种互补的Nf 1基因工程小鼠品系，其中基于海马的学习和记忆是DA依赖性的，以确定神经元DA水平和信号传导以及小鼠空间学习以Nf 1基因剂量依赖性方式控制。总的来说，这是第一次证明，不同的生殖系NF 1基因突变差异决定神经纤维蛋白在大脑中的功能。
Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurologic condition characterized by significant clinical heterogeneity, ranging from malignant cancers to cognitive deficits. Recent studies have begun to reveal rare genotype-phenotype correlations, suggesting that the specific germline NF1 gene mutation may be one factor underlying disease heterogeneity. The purpose of this study was to define the impact of the germline NF1 gene mutation on brain neurofibromin function relevant to learning. Herein, we employ human NF1-patient primary skin fibroblasts, induced pluripotent stem cells and derivative neural progenitor cells (NPCs) to demonstrate that NF1 germline mutations have dramatic effects on neurofibromin expression. Moreover, while all NF1-patient NPCs exhibit increased RAS activation and reduced cyclic AMP generation, there was a neurofibromin dose-dependent reduction in dopamine (DA) levels. Additionally, we leveraged two complementary Nf1 genetically-engineered mouse strains in which hippocampal-based learning and memory is DA-dependent to establish that neuronal DA levels and signaling as well as mouse spatial learning are controlled in an Nf1 gene dose-dependent manner. Collectively, this is the first demonstration that different germline NF1 gene mutations differentially dictate neurofibromin function in the brain.