Weiss Joseph B, Weber Sydney J, Torres Eileen Ruth S, Marzulla Tessa, Raber Jacob
Cardiovascular Institute and Warren Alpert School of Medicine at Brown University Providence, RI 02840, USA.
Department of Behavioral Neuroscience, Oregon Health & Science University, Portland, OR 97239, USA.
Behav Brain Res. 2017 Mar 15;321:148-156. doi: 10.1016/j.bbr.2017.01.003. Epub 2017 Jan 3.
Heterozygous Neurofibromatosis 1 (NF1) loss of function mutations occur in approximately 90% of patients with neurofibromatosis. A major, disabling phenotypic consequence of reduced NF1 function is cognitive impairment; a possibly related behavioral phenotype is impaired sleep. Recent results in Drosophila have demonstrated a genetic interaction between Anaplastic Lymphoma Kinase (Alk) and NF1 for both associative learning and sleep. Inhibition of Alk improves associative learning and sleep in heterozygous NF1 mutant flies. The results in Drosophila provide a strong motivation to investigate NF1/Alk genetic interactions in mice. In Drosophila, activation of Alk by its ligand, Jelly belly (Jeb), is the physiologically relevant target of negative regulation by NF1. Therefore, we tested whether genetic inhibition of Alk in heterozygous NF1 mutant mice attenuates or rescues cognitive impairments in mice. Our results are consistent with the hypothesis that NF1 functions in mice biochemically to inhibit signaling from Alk through Ras. The cognitive phenotypes observed in heterozygous NF1 mutant mice are rescued or ameliorated by genetic inhibition of Alk activity. In two tests of hippocampus-dependent learning, the Morris water maze and extinction of contextual fear, mutation of one or both alleles of Alk was sufficient to improve performance to wild type or near wild type levels in NF1-/+ mice. In addition, in NF1 mice genetic inhibition of Alk improves circadian activity levels. These data are intriguing in light of the circadian alterations seen in NF1 patients and indicate that inhibition of Alk activity may cognitively benefit patients with Neurofibromatosis 1.
约90%的神经纤维瘤病患者存在杂合型神经纤维瘤病1型（NF1）功能丧失突变。NF1功能降低的一个主要的、导致残疾的表型后果是认知障碍；一种可能相关的行为表型是睡眠障碍。果蝇的最新研究结果表明，间变性淋巴瘤激酶（Alk）与NF1在联想学习和睡眠方面存在遗传相互作用。抑制Alk可改善杂合型NF1突变果蝇的联想学习和睡眠。果蝇的研究结果为在小鼠中研究NF1/Alk遗传相互作用提供了强大动力。在果蝇中，Alk被其配体Jelly belly（Jeb）激活是NF1负调控的生理相关靶点。因此，我们测试了在杂合型NF1突变小鼠中对Alk进行基因抑制是否能减轻或挽救小鼠的认知障碍。我们的结果与以下假设一致：NF1在小鼠中通过生化方式抑制Alk通过Ras的信号传导。通过对Alk活性进行基因抑制，可挽救或改善杂合型NF1突变小鼠中观察到的认知表型。在两项依赖海马体的学习测试中，即莫里斯水迷宫实验和情境恐惧消退实验中，Alk一个或两个等位基因的突变足以使NF1杂合小鼠的表现提高到野生型或接近野生型水平。此外，在NF1小鼠中，对Alk进行基因抑制可提高昼夜活动水平。鉴于NF1患者出现的昼夜节律改变，这些数据很有趣，并表明抑制Alk活性可能对神经纤维瘤病1型患者在认知方面有益。
