Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Penn Chronobiology, Howard Hughes Medical Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Biology, Loyola University, Chicago, IL, USA.
Cell Rep. 2018 Mar 27;22(13):3416-3426. doi: 10.1016/j.celrep.2018.03.014.
Loss of the Neurofibromatosis 1 (Nf1) protein, neurofibromin, in Drosophila disrupts circadian rhythms of locomotor activity without impairing central clock function, suggesting effects downstream of the clock. However, the relevant cellular mechanisms are not known. Leveraging the discovery of output circuits for locomotor rhythms, we dissected cellular actions of neurofibromin in recently identified substrates. Herein, we show that neurofibromin affects the levels and cycling of calcium in multiple circadian peptidergic neurons. A prominent site of action is the pars intercerebralis (PI), the fly equivalent of the hypothalamus, with cell-autonomous effects of Nf1 in PI cells that secrete DH44. Nf1 interacts genetically with peptide signaling to affect circadian behavior. We extended these studies to mammals to demonstrate that mouse astrocytes exhibit a 24-hr rhythm of calcium levels, which is also attenuated by lack of neurofibromin. These findings establish a conserved role for neurofibromin in intracellular signaling rhythms within the nervous system.
神经纤维瘤病 1 型（Nf1）蛋白神经纤维瘤失活会破坏果蝇的昼夜节律性运动活动，而不会损害中央时钟功能，表明其作用发生在时钟的下游。然而，相关的细胞机制尚不清楚。利用运动节律输出回路的发现，我们在最近确定的底物中解析了神经纤维瘤的细胞作用。在此，我们表明神经纤维瘤会影响多个昼夜节律肽能神经元中的钙水平及其循环。一个主要作用部位是脑间部（PI），相当于果蝇的下丘脑，PI 细胞中 DH44 分泌的 Nf1 具有细胞自主作用。Nf1 与肽信号遗传相互作用以影响昼夜节律行为。我们将这些研究扩展到哺乳动物，以证明小鼠星形胶质细胞表现出钙水平的 24 小时节律，而缺乏神经纤维瘤则会减弱这种节律。这些发现确立了神经纤维瘤在神经系统内细胞内信号节律中的保守作用。
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